Search by property

This page provides a simple browsing interface for finding entities described by a property and a named value. Other available search interfaces include the page property search, and the ask query builder.

List of results

Zhao 2019 Pharmacol Res + (As one classic anticancer drug, clinical a … As one classic anticancer drug, clinical application of Doxorubicin (Dox) is limited due to its side effects. In our previous work, we have investigated the drug targets to treat Dox-induced cardiotoxicity, hepatotoxicity and nephrotoxicity. In this paper, the mechanisms and new drug-target associated with Dox-induced hepatotoxicity were explored. The results showed that Dox markedly inhibited cell viability and cellular respiration, induced cell morphologic change and increased ROS level. Moreover, Dox increased ALT and AST levels, caused pathological damage, increased MDA level and decreased SOD level in mice. Mechanism investigation showed that Dox markedly up-regulated the expression level of miR-128-3p, down-regulated Sirt1 expression level and affected the protein levels of Nrf2, Keap1, Sirt3, NQO1 and HO-1 to cause oxidative stress in liver. Furthermore, double-luciferase reporter assay, and co-transfection test showed that miR-128-3p directly targeted Sirt1. In addition, miR-128-3p mimics in AML-12 cells enhanced Dox-induced oxidative damage via inhibiting cellular respiration, increasing ROS level and mitochondrial superoxide formation. The protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1 in miR-128-3p mimic + Dox group were decreased compared with Dox group. Transfection of miR-128-3p inhibitor weakened Dox-induced oxidative damage via increasing cellular respiration, suppressing cellular ROS level and mitochondrial superoxide formation. The protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1 in miR-128-3p inhibitor + Dox group were increased compared with Dox group. In mice, Dox-induced liver damage was deteriorated by miR-128-3p agomir via increasing the levels of ALT, AST, MDA, and down-regulating the protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1. While, miR-128-3p antagomir alleviated liver injury via decreasing the levels of ALT, AST, MDA, and up-regulating the protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1. Our data showed that miRNA-128-3p aggravated Dox-induced liver injury by promoting oxidative stress via targeting Sirt1, which should be considered as one new drug target to treat Dox-induced liver injury.Copyright © 2019 Elsevier Ltd. All rights reserved. 2019 Elsevier Ltd. All rights reserved.)
Shirihai 2014 Abstract MiP2014 + (As our relationship with mitochondria evol … As our relationship with mitochondria evolves, we remain fascinated by the impact of this organelle in two seemingly unrelated conditions: aging and metabolic diseases. While aging involves insufficiency of mitochondrial quality control and turnover mechanisms (such as autophagy), type II diabetes and obesity are influenced by the ability of the organism to deal with excess nutrient environment. The observation that both conditions are impacted by the duration of exposure to excess nutrient environment raises the question: Are the tasks of handling nutrients in excess and maintaining quality control ever in conflict? Mitochondria go through continuous cycles of selective fusion and fission, referred to as the “mitochondrial life cycle”, to maintain the quality of their function [3-5]. Changes in mitochondrial architecture can represent an adaptation of mitochondria to respire according to the bioenergetic needs of the cell [2]. Conditions requiring high mitochondrial ATP synthesis capacity and/or efficiency, such as limited nutrient availability, are associated with mitochondrial elongation [1]; reviewed in [2], while conditions of excess energy supply and relatively low ATP demand, such as beta-cells exposed to excess nutrients, induce mitochondrial fragmentation [6]. This raises the possibility that mitochondrial fragmentation supports uncoupled respiration and thus increases energy expenditure by promoting nutrient oxidation towards heat production, rather than towards mitochondrial ATP synthesis. To test this hypothesis, we explored a system where a robust shift from coupled to uncoupled respiration and increased energy expenditure can occur. The brown adipocyte offers a unique system where transition to uncoupling can occur within minutes and in a physiological rather than pathological context. Therefore, it represents an attractive model for studying the regulation of energy expenditure induced by hormones. Our results indicate that norepinephrine induces changes to mitochondrial architecture that serve as an amplification pathway for uncoupling in brown adipocytes. Remarkably, we now have evidence that similar changes, though at a longer time scale, occur in the beta cells under excess nutrient environment. In the beta cell, nutrient–induced fragmentation is associated with increased uncoupling and the enhanced consumption of excess nutrients, thereby serving as an adaptive mechanism. Placement of bioenergetic adaptation and quality control as competing tasks of mitochondrial dynamics might provide a new mechanism, linking excess nutrient environment to progressive mitochondrial dysfunction, common to age-related diseases.sfunction, common to age-related diseases.)
Guan 1999 J Biotechnol + (As part of an overall aim to base the feed … As part of an overall aim to base the feeding of substrates to cultured animal cells on their actual metabolic needs,we have developed a stoichiometric approach centred on the macronutrients in the medium. Heat flux records theoverall metabolic activity and therefore was the sensitive indicator of changing metabolic requirement. Analyses weremade of the experimental measurements on two engineered cell lines in batch culture, the 2C11-12 macrophagehybridoma cell capable of the respiratory burst and the CHO320 constitutively producing human interferon-g. Thecrux was to construct simplified stoichiometric equations for the growth reactions to represent metabolic activity asit changed with time. Beforehand, it was essential to select the appropriate components for the equations. The choicewas then justified by constructing enthalpy balances in which the ratio of heat flux to enthalpy flux must be close tounity for validation. By combining the stoichiometric approach with heat flow measurements, it was shown boththeoretically and experimentally that the set of stoichiometric coefficients constituting a validated growth equation hasa one-to-one corresponding relationship to the metabolic activity of the average cell population. Thus, a strategy wasestablished for feeding the cells at any one time with the correct ratio of the major substrates, glucose and glutamine,in response to metabolic requirements that change with time.abolic requirements that change with time.)
DeBalsi 2017 Ageing Res Rev + (As regulators of bioenergetics in the cell … As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined.enuate the symptoms of aging are examined.)
Dickinson 2013 Cell Death Differ + (As stem cells undergo differentiation, mit … As stem cells undergo differentiation, mitochondrial DNA (mtDNA) copy number is strictly regulated in order that specialized cells can generate appropriate levels of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) to undertake their specific functions. It is not understood whether tumor-initiating cells regulate their mtDNA in a similar manner or whether mtDNA is essential for tumorigenesis. We show that human neural stem cells (hNSCs) increased their mtDNA content during differentiation in a process that was mediated by a synergistic relationship between the nuclear and mitochondrial genomes and results in increased respiratory capacity. Differentiating multipotent glioblastoma cells failed to match the expansion in mtDNA copy number, patterns of gene expression and increased respiratory capacity observed in hNSCs. Partial depletion of glioblastoma cell mtDNA rescued mtDNA replication events and enhanced cell differentiation. However, prolonged depletion resulted in impaired mtDNA replication, reduced proliferation and induced the expression of early developmental and pro-survival markers including POU class 5 homeobox 1 (OCT4) and sonic hedgehog (SHH). The transfer of glioblastoma cells depleted to varying degrees of their mtDNA content into immunocompromised mice resulted in tumors requiring significantly longer to form compared with non-depleted cells. The number of tumors formed and the time to tumor formation was relative to the degree of mtDNA depletion. The tumors derived from mtDNA depleted glioblastoma cells recovered their mtDNA copy number as part of the tumor formation process. These outcomes demonstrate the importance of mtDNA to the initiation and maintenance of tumorigenesis in glioblastoma multiforme. tumorigenesis in glioblastoma multiforme.)
Rodgers 2021 Elife + (As the final outputs of the Reproducibility Project: Cancer Biology are published, it is clear that preclinical research in cancer biology is not as reproducible as it should be.)
Rai 2022 G3 (Bethesda) + (As the fruit fly, Drosophila melanogaster, … As the fruit fly, Drosophila melanogaster, progresses from one life stage to the next, many of the enzymes that compose intermediary metabolism undergo substantial changes in both expression and activity. These predictable shifts in metabolic flux allow the fly meet stage-specific requirements for energy production and biosynthesis. In this regard, the enzyme glycerol-3-phosphate dehydrogenase 1 (GPDH1) has been the focus of biochemical genetics studies for several decades and, as a result, is one of the most well-characterized Drosophila enzymes. Among the findings of these earlier studies is that GPDH1 acts throughout the fly lifecycle to promote mitochondrial energy production and triglyceride accumulation while also serving a key role in maintaining redox balance. Here, we expand upon the known roles of GPDH1 during fly development by examining how depletion of both the maternal and zygotic pools of this enzyme influences development, metabolism, and viability. Our findings not only confirm previous observations that Gpdh1 mutants exhibit defects in larval development, lifespan, and fat storage but also reveal that GPDH1 serves essential roles in oogenesis and embryogenesis. Moreover, metabolomics analysis reveals that a Gpdh1 mutant stock maintained in a homozygous state exhibits larval metabolic defects that significantly differ from those observed in the F1 mutant generation. Overall, our findings highlight unappreciated roles for GPDH1 in early development and uncover previously undescribed metabolic adaptations that could allow flies to survive the loss of this key enzyme.es to survive the loss of this key enzyme.)
MitoEAGLE Task Group States and rates + (As the knowledge base and importance of mi … As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow guidelines of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols to the nomenclature of classical bioenergetics. We endeavour to provide a balanced view on mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of databases of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery.ucation, and ultimately further discovery.)
Radogna 2021 Methods Mol Biol + (As the powerhouse of the cell, mitochondri … As the powerhouse of the cell, mitochondria, plays a crucial role in many aspects of life, whereby mitochondrial dysfunctions are associated with pathogenesis of many diseases, like neurodegenerative diseases, obesity, cancer, and metabolic as well as cardiovascular disorders. Mitochondria analysis frequently starts with isolation and enrichment procedures, which have become increasingly important in biomedical research. Unfortunately, isolation procedures can easily cause changes in the structural integrity of mitochondria during in vitro handling having impact on their function. This carries the risk that conclusions about isolated mitochondria may be drawn on the basis of experimental artifacts. Here we critically review a commonly used isolation procedure for mitochondria utilizing differential (gradient) centrifugation and depict major challenges to achieve "functional" mitochondria as basis for comprehensive physiological studies.s for comprehensive physiological studies.)
Lehr 2021 Methods Mol Biol + (As the powerhouse of the cell, mitochondri … As the powerhouse of the cell, mitochondria, plays a crucial role in many aspects of life, whereby mitochondrial dysfunctions are associated with pathogenesis of many diseases, like neurodegenerative diseases, obesity, cancer, and metabolic as well as cardiovascular disorders. Mitochondria analysis frequently starts with isolation and enrichment procedures, which have become increasingly important in biomedical research. Unfortunately, isolation procedures can easily cause changes in the structural integrity of mitochondria during ''in vitro'' handling having impact on their function. This carries the risk that conclusions about isolated mitochondria may be drawn on the basis of experimental artifacts. Here we critically review a commonly used isolation procedure for mitochondria utilizing differential (gradient) centrifugation and depict major challenges to achieve "functional" mitochondria as basis for comprehensive physiological studies.s for comprehensive physiological studies.)
De Jager 2017 Adv Exp Med Biol + (As ultraviolet (UV) radiation is naturally … As ultraviolet (UV) radiation is naturally and ubiquitously emitted by the sun, almost everyone is exposed to it on a daily basis, and it is necessary for normal physiological function. Human exposure to solar UV radiation thus has important health implications. The generation of reactive oxygen species (ROS) by UV radiation is one of the mechanisms through which UV light can manifest its possible detrimental effects on health. When an imbalance develops due to ROS generation exceeding the body's antioxidant defence mechanisms, oxidative stress can develop. Oxidative stress can lead to cellular damage (e.g. lipid peroxidation and DNA fragmentation), apoptosis and cell death. Broadly UV can induce ROS by affecting the cellular components directly or by means of photosensitization mechanisms. More specifically UV light can induce ROS by affecting the enzyme catalase and up-regulating nitric oxide synthase (NOS) synthesis. It may also cause a decrease in protein kinase C (PKC) expression leading to increased ROS production. UVR is capable of modifying DNA and other chromophores resulting in elevated ROS levels. The effects of raised ROS levels can vary based on the intracellular oxidant status of the cell. It is therefore important to protect yourself against the potentially harmful effects of UV light as it can lead to pathological UV-induced ROS production.to pathological UV-induced ROS production.)
Levett 2012 FASEB J + (Ascent to high altitude is associated with … Ascent to high altitude is associated with a fall in the partial pressure of inspired oxygen (hypobaric hypoxia). For oxidative tissues such as skeletal muscle, resultant cellular hypoxia necessitates acclimatization to optimize energy metabolism and restrict oxidative stress, with changes in gene and protein expression that alter mitochondrial function. It is known that lowlanders returning from high altitude have decreased muscle mitochondrial densities, yet the underlying transcriptional mechanisms and time course are poorly understood. To explore these, we measured gene and protein expression plus ultrastructure in muscle biopsies of lowlanders at sea level and following exposure to hypobaric hypoxia. Subacute exposure (19 d after initiating ascent to Everest base camp, 5300 m) was not associated with mitochondrial loss. After 66 d at altitude and ascent beyond 6400 m, mitochondrial densities fell by 21%, with loss of 73% of subsarcolemmal mitochondria. Correspondingly, levels of the transcriptional coactivator PGC-1α fell by 35%, suggesting down-regulation of mitochondrial biogenesis. Sustained hypoxia also decreased expression of electron transport chain complexes I and IV and UCP3 levels. We suggest that during subacute hypoxia, mitochondria might be protected from oxidative stress. However, following sustained exposure, mitochondrial biogenesis is deactivated and uncoupling down-regulated, perhaps to improve the efficiency of ATP production. improve the efficiency of ATP production.)
Mui 2018 Am J Mens Health + (Asian Americans develop health complicatio … Asian Americans develop health complications at lower BMIs than other racial/ethnic groups. Given increasing overweight and obesity rates nationwide, growing numbers of Asian American men, and limited research on overweight and obesity in this population, understanding overweight and obesity differences across Asian subgroups of men is crucial to advancing health equity. This study examined overweight and obesity prevalence both among ethnic subgroups of Asian American men and compared to non-Hispanic White (NHW) men. Prevalence ratios were derived from 2002 to 2015 National Health Interview Survey data to determine associations between race/ethnicity and (a) overweight, and (b) obesity, across (''N'' = 221,376) racial/ethnic groups of men (Chinese; Filipino; Asian Indian; Other Asian; NHW). Overweight and obesity for all Asian subgroups were defined using Asian-specific BMI cut points. Adjusted overweight prevalence was higher across all Asian subgroups compared to NHW men, except Filipinos. No significant pairwise relationships were observed for overweight prevalence among Asian subgroups. Filipinos had higher adjusted obesity prevalence compared to NHW men. Comparing among Asian American men, Asian Indians and Other Asians had higher adjusted obesity prevalence relative to Chinese. Filipinos had higher adjusted obesity prevalence compared to all other Asian subgroups (Chinese; Asian Indian; Other Asian). The current findings highlight the need for use of (a) WHO-recommended Asian-specific BMI cut points and (b) data disaggregated by Asian American subgroup, to provide more accurate depictions of overweight and obesity rates and associated health risks. Accounting for subgroup differences is necessary to ensure Asian American men receive equitable, appropriate care.n men receive equitable, appropriate care.)
Misra 2009 J Assoc Physicians India + (Asian Indians exhibit unique features of o … Asian Indians exhibit unique features of obesity; excess body fat, abdominal adiposity, increased subcutaneous and intra-abdominal fat, and deposition of fat in ectopic sites (liver, muscle, etc.). Obesity is a major driver for the widely prevalent metabolic syndrome and type 2 diabetes mellitus (T2DM) in Asian Indians in India and those residing in other countries. Based on percentage body fat and morbidity data, limits of normal BMI are narrower and lower in Asian Indians than in white Caucasians. In this consensus statement, we present revised guidelines for diagnosis of obesity, abdominal obesity, the metabolic syndrome, physical activity, and drug therapy and bariatric surgery for obesity in Asian Indians after consultations with experts from various regions of India belonging to the following medical disciplines; internal medicine, metabolic diseases, endocrinology, nutrition, cardiology, exercise physiology, sports medicine and bariatric surgery, and representing reputed medical institutions, hospitals, government funded research institutions, and policy making bodies. It is estimated that by application of these guidelines, additional 10-15 % of Indian population would be labeled as overweight/obese and would require appropriate management. Application of these guidelines on countrywide basis is also likely to have a deceleration effect on the escalating problem of T2DM and cardiovascular disease. These guidelines could be revised in future as appropriate, after another large and countrywide consensus process. Till that time, these should be used by clinicians, researchers and policymakers dealing with obesity and related diseases.dealing with obesity and related diseases.)
Farrugia 2019 Sci Rep + (Aspirin is a widely used anti-inflammatory … Aspirin is a widely used anti-inflammatory and antithrombotic drug also known in recent years for its promising chemopreventive antineoplastic properties, thought to be mediated in part by its ability to induce apoptotic cell death. However, the full range of mechanisms underlying aspirin's cancer-preventive properties is still elusive. In this study, we observed that aspirin impaired both the synthesis and transport of acetyl-coenzyme A (acetyl-CoA) into the mitochondria of manganese superoxide dismutase (MnSOD)-deficient Saccharomyces cerevisiae EG110 yeast cells, but not of the wild-type cells, grown aerobically in ethanol medium. This occurred at both the gene level, as indicated by microarray and qRT-PCR analyses, and at the protein level as indicated by enzyme assays. These results show that in redox-compromised MnSOD-deficient yeast cells, but not in wild-type cells, aspirin starves the mitochondria of acetyl-CoA and likely causes energy failure linked to mitochondrial damage, resulting in cell death. Since acetyl-CoA is one of the least-studied targets of aspirin in terms of the latter's propensity to prevent cancer, this work may provide further mechanistic insight into aspirin's chemopreventive behavior with respect to early stage cancer cells, which tend to have downregulated MnSOD and are also redox-compromised.ated MnSOD and are also redox-compromised.)
Lichtenberger 2019 Cancer Res + (Aspirin, when administered at low doses, h … Aspirin, when administered at low doses, has emerged as a powerful anticancer drug due to both chemopreventive activity against many forms of cancer and its ability to block metastases when administered postdiagnosis. Platelets, which are often elevated in circulation during the latter stages of cancer, are known to promote epithelial-mesenchymal transition, cancer cell growth, survival in circulation, and angiogenesis at sites of metastases. Low-dose aspirin has been demonstrated to block this procarcinogenic action of platelets. In this article, we present evidence that aspirin's unique ability to irreversibly inhibit platelet cyclooxygenase-1 is a key mechanism by which aspirin exerts anticancer activity. which aspirin exerts anticancer activity.)
Chojnacka 2022 Mol Biol Cell + (Assembly of the dimeric complex III (CIII& … Assembly of the dimeric complex III (CIII2) in the mitochondrial inner membrane is an intricate process in which several accessory proteins are involved as assembly factors. Despite numerous studies, this process has yet to be fully understood. Here we report the identification of human OCIAD2 (ovarian carcinoma immunoreactive antigen-like protein 2) as an assembly factor for CIII2. OCIAD2 was found to be deregulated in several carcinomas and also in some neurogenerative disorders; however, its nonpathological role had not been elucidated. We have shown that OCIAD2 localizes to mitochondria and interacts with electron transport chain (ETC) proteins. Complete loss of OCIAD2 using gene editing in HEK293 cells resulted in abnormal mitochondrial morphology, a substantial decrease of both CIII2 and supercomplex III2+IV, and a reduction in CIII enzymatic activity. Identification of OCIAD2 as a protein required for assembly of functional CIII2 provides a new insight into the biogenesis and architecture of the ETC. Elucidating the mechanism of OCIAD2 action is important both for the understanding of cellular metabolism and for an understanding of its role in malignant transformation.understanding of cellular metabolism and for an understanding of its role in malignant transformation.)
Brand 2011 Biochem J + (Assessing mitochondrial dysfunction requir … Assessing mitochondrial dysfunction requires definition of the dysfunction to be investigated. Usually, it is the ability of the mitochondria to make ATP appropriately in response to energy demands. Where other functions are of interest, tailored solutions are required. Dysfunction can be assessed in isolated mitochondria, in cells or in vivo, with different balances between precise experimental control and physiological relevance. There are many methods to measure mitochondrial function and dysfunction in these systems. Generally, measurements of fluxes give more information about the ability to make ATP than do measurements of intermediates and potentials. For isolated mitochondria, the best assay is mitochondrial respiratory control: the increase in respiration rate in response to ADP. For intact cells, the best assay is the equivalent measurement of cell respiratory control, which reports the rate of ATP production, the proton leak rate, the coupling efficiency, the maximum respiratory rate, the respiratory control ratio and the spare respiratory capacity. Measurements of membrane potential provide useful additional information. Measurement of both respiration and potential during appropriate titrations enables the identification of the primary sites of effectors and the distribution of control, allowing deeper quantitative analyses. Many other measurements in current use can be more problematic, as discussed in the present review.matic, as discussed in the present review.)
Niehusmann 2011 Epilepsy Behav + (Assessment for epilepsy surgery may requir … Assessment for epilepsy surgery may require invasive measures such as implantation of intracranial electrodes or the Wada test. These investigations are commonly well tolerated. However, complications, including visual disturbances of various etiologies, have been reported. Here we describe two patients with pharmacoresistant temporal lobe epilepsy (TLE) who displayed loss of vision in the context of presurgical assessment and in whom mutations associated with Leber's hereditary optic neuropathy (LHON) were detected. Genetic analysis revealed in one patient the frequent mitochondrial G11778A LHON mutation in ND4. In the second patient, the mitochondrial C4640A mutation in ND2 was detected. This rare LHON mutation enhanced the sensitivity of the patient's muscle and brain tissue to amobarbital, a known blocker of the mitochondrial respiratory chain. Mitochondrial dysfunction has been reported in epilepsy. Thus, the presence of LHON mutations can be a rare cause of visual disturbances in patients with epilepsy and may have predisposed to development of epilepsy.ve predisposed to development of epilepsy.)
Cikankova 2019 Naunyn Schmiedebergs Arch Pharmacol + (Assessment of drug-induced mitochondrial d … Assessment of drug-induced mitochondrial dysfunctions is important in drug development as well as in the understanding of molecular mechanism of therapeutic or adverse effects of drugs. The aim of this study was to investigate the effects of three typical antipsychotics (APs) and seven atypical APs on mitochondrial bioenergetics. The effects of selected APs on citrate synthase, electron transport chain complexes (ETC), and mitochondrial complex I- or complex II-linked respiratory rate were measured using mitochondria isolated from pig brain. Complex I activity was decreased by chlorpromazine, haloperidol, zotepine, aripiprazole, quetiapine, risperidone, and clozapine. Complex II + III was significantly inhibited by zotepine, aripiprazole, quetiapine, and risperidone. Complex IV was inhibited by zotepine, chlorpromazine, and levomepromazine. Mitochondrial respiratory rate was significantly inhibited by all tested APs, except for olanzapine. Typical APs did not exhibit greater efficacy in altering mitochondrial function compared to atypical APs except for complex I inhibition by chlorpromazine and haloperidol. A comparison of the effects of APs on individual respiratory complexes and on the overall mitochondrial respiration has shown that mitochondrial functions may not fully reflect the disruption of complexes of ETC, which indicates AP-induced modulation of other mitochondrial proteins. Due to the complicated processes associated with mitochondrial activity, it is necessary to measure not only the effect of the drug on individual mitochondrial enzymes but also the respiration rate of the mitochondria or a similar complex process. The experimental approach used in the study can be applied to mitochondrial toxicity testing of newly developed drugs.toxicity testing of newly developed drugs.)
Perry 2011 Biochem J + (Assessment of mitochondrial ADP-stimulated … Assessment of mitochondrial ADP-stimulated respiratory kinetics in permeabilized fibre (pfi) bundles is increasingly used in clinical diagnostic and basic research settings. However, estimates of the ''K''m for ADP vary considerably (~20-300 μM) and tend to overestimate respiration at rest. Noting that pfi bundles spontaneously contract during respiration experiments, we systematically determined the impact of contraction, temperature and oxygenation on ADP-stimulated respiratory kinetics. BLEB ('''blebbistatin'''), a myosin II ATPase inhibitor, blocked contraction under all conditions and yielded high ''K''m values for ADP of >~250 and ~80 μM in red and white rat pfi bundles respectively. In the absence of BLEB, pfi bundles contracted and the ''K''m for ADP decreased ~2-10-fold in a temperature-dependent manner. pfi bundles were sensitive to hyperoxia (increased ''K''m) in the absence of BLEB (contracted) at 30 °C but not 37 °C. In pfi bundles from humans, contraction elicited high sensitivity to ADP (''K''m<100 μM), whereas blocking contraction (+BLEB) and including a phosphocreatine/creatine ratio of 2:1 to mimic the resting energetic state yielded a ''K''m for ADP of ~1560 μM, consistent with estimates of ''in vivo'' resting respiratory rates of <1% maximum. These results demonstrate that the sensitivity of muscle to ADP varies over a wide range in relation to contractile state and cellular energy charge, providing evidence that enzymatic coupling of energy transfer within skeletal muscle becomes more efficient in the working state.ing evidence that enzymatic coupling of energy transfer within skeletal muscle becomes more efficient in the working state.)
Meszaros 2018 Mt Med Hinxton + (Assessment of mitochondrial respiration at … Assessment of mitochondrial respiration at higher-than-physiological oxygen (O2) concentrations has become a standard in biomedical research. In contrast, the impact of mitochondrial O2 kinetics on (patho)physiology is largely neglected. To facilitate further studies, we developed the automatized software module ''O2'''kinetics'''''. Using this advanced tool, we re-evaluated the O2 dependence of mitochondrial respiration in various respiratory states, experimental conditions, and in the presence of cytochrome c oxidase (CIV) inhibitors.Mitochondria isolated from mouse brain, heart and liver were incubated at 37 °C in Oroboros O2k High-Resolution FluoRespirometers. Using substrate-uncoupler-inhibitor titration (SUIT) protocols with various fuel substrate combinations in OXPHOS-, LEAK- and ET-states, we investigated the effect of pathway and coupling control on mitochondrial ''p50'' (O2 partial pressure at half-maximum O2 flux, ''JO2''). Kinetic data was obtained during aerobic-anaerobic transitions with high time-resolution at data sampling intervals of 0.2 s. ''p50'' values were calculated using the ''O2'''kinetics''''' software for automatic correction and calibration steps. Depending on experimental temperature and respiratory state, ''p50'' ranged from 0.006 to 0.07 kPa for NADH-linked LEAK respiration with glutamate&malate, N(GM)''L'', and NADH-&succinate-linked OXPHOS capacity including GM and pyruvate, NS(GMP)''P'', in agreement with and extending data published previously. In heart and liver mitochondria, the ''p50'' was higher in OXPHOS- compared to LEAK-states, increasing proportionally with CIV turnover. Upon inhibition of CIV, ''p50'' increased several-fold up to 0.15 kPa, NS(GM)''P'', which was not reflected in ''JO2'' at kinetic O2 saturation. In diagnostic experiments, increasing ''p50'' values correlated well with decreasing CIV activity, as measured upon addition of ascorbate and TMPD.Mitochondrial ''p50'' measurement is a quick, highly accurate and sensitive way for early detection of reduced CIV excess capacity, as affinity of mitochondria for O2 decreases already at a slight CIV inhibition. Determination of mitochondrial O2 dependence has implications in a wide range of biomedical research topics, particularly in studies with CIV mutations (e.g. Leigh syndrome), or with small inhibitory molecules (nitric oxide). ''O2'''kinetics''''' provides a fast and simple method for the detection of CIV impairment and extends standard OXPHOS analysis to the intracellular O2 regime ''in vivo'', reflecting low physiological O2 concentrations or tissue hypoxia.tory molecules (nitric oxide). ''O2'''kinetics''''' provides a fast and simple method for the detection of CIV impairment and extends standard OXPHOS analysis to the intracellular O2 regime ''in vivo'', reflecting low physiological O2 concentrations or tissue hypoxia.)
Daradics 2022 PLoS One + (Associating Liver Partition and Portal vei … Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) is a modification of two-stage hepatectomy profitable for patients with inoperable hepatic tumors by standard techniques. Unfortunately, initially poor postoperative outcome was associated with ALPPS, in which mitochondrial dysfunction played an essential role. Inhibition of cyclophilins has been already proposed to be efficient as a mitochondrial therapy in liver diseases. To investigate the effect of Cyclophilin D (CypD) depletion on mitochondrial function, biogenesis and liver regeneration following ALPPS a CypD knockout (KO) mice model was created.Male wild type (WT) (n = 30) and CypD KO (n = 30) mice underwent ALPPS procedure. Animals were terminated pre-operatively and 24, 48, 72 or 168 h after the operation. Mitochondrial functional studies and proteomic analysis were performed. Regeneration rate and mitotic activity were assessed.The CypD KO group displayed improved mitochondrial function, as both ATP production (P < 0.001) and oxygen consumption (P < 0.05) were increased compared to the WT group. The level of mitochondrial biogenesis coordinator peroxisome proliferator-activated receptor γ co-activator 1-α (PGC1-α) was also elevated in the CypD KO group (P < 0.001), which resulted in the induction of the mitochondrial oxidative phosphorylation system. Liver growth increased in the CypD KO group compared to the WT group (P < 0.001).Our study demonstrates the beneficial effect of CypD depletion on the mitochondrial vulnerability following ALPPS. Based on our results we propose that CypD inhibition should be further investigated as a possible mitochondrial therapy following ALPPS.d as a possible mitochondrial therapy following ALPPS.)
Budai 2018 Br J Surg + (Associating liver partition and portal vei … Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage strategy to induce rapid regeneration of the remnant liver. The technique has been associated with high mortality and morbidity rates. This study aimed to evaluate mitochondrial function, biogenesis and morphology during ALPPS-induced liver regeneration.Male Wistar rats (n = 100) underwent portal vein ligation (PVL) or ALPPS. The animals were killed at 0 h (without operation), and 24, 48, 72 or 168 h after intervention. Regeneration rate and proliferation index were assessed. Mitochondrial oxygen consumption and adenosine 5'-triphosphate (ATP) production were measured. Mitochondrial biogenesis was evaluated by protein level measurements of peroxisome proliferator-activated receptor γ co-activator (PGC) 1-α, nuclear respiratory factor (NRF) 1 and 2, and mitochondrial transcription factor α. Mitochondrial morphology was evaluated by electron microscopy.Regeneration rate and Ki-67 index were significantly raised in the ALPPS group compared with the PVL group (regeneration rate at 168 h: mean(s.d.) 291·2(21·4) versus 245·1(13·8) per cent, P < 0·001; Ki-67 index at 24 h: 86·9(4·6) versus 66·2(4·9) per cent, P < 0·001). In the ALPPS group, mitochondrial function was impaired 48 h after the intervention compared with that in the PVL group (induced ATP production); (complex I: 361·9(72·3) versus 629·7(165·8) nmol per min per mg, P = 0·038; complex II: 517·5(48·8) versus 794·8(170·4) nmol per min per mg, P = 0·044). Markers of mitochondrial biogenesis were significantly lower 48 and 72 h after ALPPS compared with PVL (PGC1-α at 48 h: 0·61-fold decrease, P = 0·045; NRF1 at 48 h: 0·48-fold decrease, P = 0·028). Mitochondrial size decreased significantly after ALPPS (0·26(0·05) versus 0·40(0·07) μm2 ; P = 0·034).Impaired mitochondrial function and biogenesis, along with the rapid energy-demanding cell proliferation, may cause hepatocyte dysfunction after ALPPS. Surgical relevance Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a well known surgical strategy that combines liver partition and portal vein ligation. This method induces immense regeneration in the future liver remnant. The rapid volume increase is of benefit for resectability, but the mortality and morbidity rates of ALPPS are strikingly high. Moreover, lagging functional recovery of the remnant liver has been reported recently. In this translational study, ALPPS caused an overwhelming inflammatory response that interfered with the peroxisome proliferator-activated receptor γ co-activator 1-α-coordinated, stress-induced, mitochondrial biogenesis pathway. This resulted in the accumulation of immature and malfunctioning mitochondria in hepatocytes during the early phase of liver regeneration (bioenergetic destabilization). These findings might explain some of the high morbidity if confirmed in patients.© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)
Skulachev 2014 Abstract MiP2014 + (Assuming that mitochondria are sources of … Assuming that mitochondria are sources of reactive oxygen species (ROS), causing a number of pathologies, predicts that mitochondria-targeted antioxidants should decrease intracellular ROS and cure humans suffering from various ROS-linked diseases much stronger than non-targeted antioxidants or antioxidants targeted to compartments other than mitochondria. The first observation of this kind was done by Murphy’s group, where mitochondria-targeted CoQ derivative MitoQ was found to inhibit ROS-induced apoptosis of cell cultures at 5∙102 times lower concentration than non-targeted CoQ [1]. Later, Chernyak’s group in our laboratory showed an even larger difference between mitochondria-targeted plastoquinones (SkQ1 or SkQR1) and non-targeted N-acetyl cysteine (NAC) and trolox [2-4]. The stronger effect of SkQs, compared to MitoQ, was mainly due to a much larger window between anti- and prooxidant activities of these quinones. A 106 difference between doses of SkQ1 and NAC was shown in our group by Kopnin and coworkers, who studied an increase in lifespan of p53-/- mice who died due to lymphoma [5]. Such a great advantage of SkQ1 over NAC could be predicted if one takes into account that (1) the antioxidant effect of SkQ1 results in a prevention of the chain reaction of cardiolipin peroxidation, localized in the inner mitochondrial membrane; and (2) extracellular SkQ1, in contrast to NAC, electrophoretically accumulates by a factor of 10 in cytosol, 103 in the mitochondrial matrix and 104 in the membrane, because of a high octanol/water distribution coefficient. As a result, SkQ1 concentration in the inner mitochondrial membrane can be 108 (10∙103∙104) times higher than extramitochondrial [SkQ1] [6,7]. Large differences between acting concentrations of SkQ1 and those of vitamin E or NAC were revealed by Kolosova and coworkers when studying progeric OXYS rats (age-dependent development of cataract, retinopathy and an IGF-1 decrease were investigated) [5-8]. Rabinovich and his colleagues succeeded in an ''in vivo'' targeting of catalase to mitochondria [9-12]. In particular, an antiprogeric effect was observed in “mutator” mice defective in the proof-reading domain of mitochondrial DNA polymerase [12]. Such mice were shown to have an elevated content of mitochondrial H2O2 [13]. Targeting of catalase to nucleus or peroxisomes proved to be much less effective than to mitochondria [9]. The final aim of ROS studies is certainly the treatment of ROS-induced pathologies in humans. There is already a precedent when a mitochondria-targeted antioxidant - eye drops Visomitin containing 250 nM SkQ1, which is an efficient treatment of the previously incurable disease “dry eye syndrome” [14,15] - were officially recommended as a medicine and became available in pharmacies. Clinical trials of this drug showed that it is also beneficial in two other age-related diseases, i.e. cataract and glaucoma. Again, SkQ1 proved to be much more efficient than thymolol, a non-targeted antioxidant. beneficial in two other age-related diseases, i.e. cataract and glaucoma. Again, SkQ1 proved to be much more efficient than thymolol, a non-targeted antioxidant.)
Ederle 2019 J Clin Med + (Asthma is a chronic inflammatory lung synd … Asthma is a chronic inflammatory lung syndrome with an increasing prevalence and a rare but significant risk of death. Its pathophysiology is complex, and therefore we investigated at the systemic level a potential implication of oxidative stress and of peripheral blood mononuclear cells' (PBMC) mitochondrial function. Twenty severe asthmatic patients with severe exacerbation (GINA 4-5) and 20 healthy volunteers participated at the study. Mitochondrial respiratory chain complexes activities using different substrates and reactive oxygen species (ROS) production were determined in both groups by high-resolution respirometry and electronic paramagnetic resonance, respectively. Healthy PBMC were also incubated with a pool of plasma of severe asthmatics or healthy controls. Mitochondrial respiratory chain complexes activity (+52.45%, p = 0.015 for VADP) and ROS production (+34.3%, p = 0.02) were increased in asthmatic patients. Increased ROS did not originate mainly from mitochondria. Plasma of severe asthmatics significantly increased healthy PBMC mitochondrial dioxygen consumption (+56.8%, p = 0.031). In conclusion, such asthma endotype, characterized by increased PMBCs mitochondrial oxidative capacity and ROS production likely related to a plasma constituent, may reflect activation of the immune system. Further studies are needed to determine whether increased PBMC mitochondrial respiration might have protective effects, opening thus new therapeutic approaches.tive effects, opening thus new therapeutic approaches.)
Cabral-Costa 2022 MitoFit + (Astrocytes are a heterogenous population o … Astrocytes are a heterogenous population of macroglial cells spread throughout the central nervous system with diverse functions, expression signatures, and intricate morphologies. Their subcellular compartments contain a distinct range of mitochondria, with functional microdomains exhibiting widespread activities, such as controlling local metabolism and Ca2+ signaling. Ca2+ is an ion of utmost importance, both physiologically and pathologically, and participates in critical central nervous system processes, including synaptic plasticity, neuron-astrocyte integration, excitotoxicity, and mitochondrial physiology and metabolism. The mitochondrial Ca2+ handling system is formed by the mitochondrial Ca2+ uniporter complex (MCUc), which mediates Ca2+ influx, and the mitochondrial Na+/Ca2+ exchanger (NCLX), responsible for most mitochondrial Ca2+ efflux, as well as additional components, including the mitochondrial permeability transition pore (mtPTP). Over the last decades, mitochondrial Ca2+ handling has been shown to be key for brain homeostasis, acting centrally in physiopathological processes such as astrogliosis, astrocyte-neuron activity integration, energy metabolism control, and neurodegeneration. In this review we discuss the current state of knowledge of the mitochondrial Ca2+ handling system molecular composition, highlighting its impact on astrocytic homeostasis. state of knowledge of the mitochondrial Ca2+ handling system molecular composition, highlighting its impact on astrocytic homeostasis. )
Vandenberg 2021 Neurochem Int + (Astrocytes, glial cells within the brain, … Astrocytes, glial cells within the brain, work to protect neurons during high levels of activity by maintaining oxidative homeostasis via regulation of energy supply and antioxidant systems. In recent years, mitochondrial dysfunction has been highlighted as an underlying factor of pathology in many neurological disorders. In animal studies of Fragile X Syndrome (FXS), the leading genetic cause of autism, higher levels of reactive oxygen species, lipid peroxidation, and protein oxidation within the brain indicates that mitochondria function is also altered in FXS. Despite their integral contribution to redox homeostasis within the CNS, the role of astrocytes on the occurrence or progression of neurodevelopmental disorders in this way is rarely considered. This study specifically examines changes to astrocyte mitochondrial function and antioxidant expression that may occur in FXS. Using the Fmr1 knockout (KO) mouse model, mitochondrial respiration and reactive oxygen species (ROS) emission were analyzed in primary cortical astrocytes. While mitochondrial respiration was similar between genotypes, ROS emission was significantly elevated in Fmr1 KO astrocytes. Notably, NADPH-oxidase 2 expression in Fmr1 KO astrocytes was also enhanced but only changes in catalase antioxidant enzyme expression were noted. Characterization of astrocyte factors involved in redox imbalance is invaluable to uncovering potential sources of oxidative stress in neurodevelopmental disorders and more specifically, the intercellular mechanisms that contribute to dysfunction in FXS.sms that contribute to dysfunction in FXS.)
Kunz 1997 Anal Biochem + (At 488 nm argon-ion laser excitation human … At 488 nm argon-ion laser excitation human mononuclear cells emit flavoprotein-related autofluorescence signals. Approximately 60% of these are caused by the mitochondrial flavoproteins α-lipoamide dehydrogenase and electron transfer flavoprotein, having differences in their fluorescence emission spectra. At the emission wavelength of 530 nm the redox changes of α-lipoamide dehydrogenase fluorescence in human mononuclear cells can be monitored by flow cytometry. This allows the estimation of the steady-state reduction level of this flavoprotein being in redox equilibrium with the mitochondrial NAD-system. We applied this method to elucidate the possible impairment of mitochondrial function in subpopulations of mononuclear cells of patients harboring deletions of the mitochondrial DNA in skeletal muscle. In the monocyte fraction of three patients and in the lymphocyte fraction of one patient we observed in the presence of the mitochondrial substrate octanoate elevated steady-state reduction levels of α-lipoamide dehydrogenase. This is an indication for the presence of respiratory chain-inhibited mitochondria in mononuclear cell subpopulations of the described patients. These data were confirmed by conventional determinations of maximal oxygen consumption rates of digitonin-permeabilized cells. Therefore, the flow cytometric determination of flavoprotein-caused autofluorescence changes is a useful and sensitive method for the detection of an impairment of mitochondrial respiratory chain in subpopulations of heterogeneous cell suspensions.lations of heterogeneous cell suspensions.)
World Health Organization 2010 IPECP + (At a time when the world is facing a short … At a time when the world is facing a shortage of health workers, policy-makers are looking for innovative strategies that can help them develop policy and programmes to bolster the global health workforce. The ''Framework for Action on Interprofessional Education and Collaborative Practice'' highlights the current status of interprofessional collaboration around the world, identifies the mechanisms that shape successful collaborative teamwork and outlines a series of action items that policy-makers can apply within their local health system (Figure 1). The goal of the Framework is to provide strategies and ideas that will help health policy-makers implement the elements of interprofessional education and collaborative practice that will be most beneficial in their own jurisdiction.* The World Health Organization (WHO) and its partners recognize interprofessional collaboration in education and practice as an innovative strategy that will play an important role in mitigating the global health workforce crisis.* Interprofessional education occurs when students from two or more professions learn about, from and with each other to enable effective collaboration and improve health outcomes.* Interprofessional education is a necessary step in preparing a “collaborative practice-ready” health workforce that is better prepared to respond to local health needs.* A collaborative practice-ready health worker is someone who has learned how to work in an interprofessional team and is competent to do so.* Collaborative practice happens when multiple health workers from different professional backgrounds work together with patients, families, carers and communities to deliver the highest quality of care. It allows health workers to engage any individual whose skills can help achieve local health goals.* After almost 50 years of enquiry, the World Health Organization and its partners acknowledge that there is sufficient evidence to indicate that effective interprofessional education enables effective collaborative practice.* Collaborative practice strengthens health systems and improves health outcomes.* Integrated health and education policies can promote effective interprofessional education and collaborative practice.* A range of mechanisms shape effective interprofessional education and collaborative practice. These include: :- supportive management practices :- identifying and supporting champions :- the resolve to change the culture and attitudes of health workers:- a willingness to update, renew and revise existing curricula :- appropriate legislation that eliminates barriers to collaborative practice.* Mechanisms that shape interprofessional education and collaborative practice are not the same in all health systems. Health policy-makers should utilize the mechanisms that are most applicable and appropriate to their own local or regional context.* Health leaders who choose to contextualize, commit and champion interprofessional education and collaborative practice position their health system to facilitate achievement of the health-related Millennium Development Goals (MDGs).* The ''Framework for Action on Interprofessional Education and Collaborative Practice'' provides policy-makers with ideas on how to implement interprofessional education and collaborative practice within their current context. ractice within their current context. )
Sharaf 2017 Aquat Toxicol + (At excess levels, zinc (Zn) disrupts mitoc … At excess levels, zinc (Zn) disrupts mitochondrial functional integrity and induces oxidative stress in aquatic organisms. Although much is known about the modulation of Zn toxicity by calcium (Ca) in fish, their interactions at the mitochondrial level have scarcely been investigated. Here we assessed the individual and combined effects of Zn and Ca on the relationship between mitochondrial respiration, ROS and membrane potential (ΔΨmt) in rainbow trout liver mitochondria. We tested if cation uptake through the mitochondrial calcium uniporter (MCU) is a prerequisite for Zn- and/or Ca-induced alteration of mitochondrial function. Furthermore, using our recently developed real-time multi-parametric method, we investigated the changes in respiration, ΔΨmt, and reactive oxygen species (ROS, as hydrogen peroxide (H2O2)) release associated with Ca-induced mitochondrial depolarization imposed by transient and permanent openings of the mitochondrial permeability transition pore (mPTP). We found that independent of the MCU, Zn precipitated an immediate depolarization of the ΔΨmt that was associated with relatively slow enhancement of H2O2 release, inhibition of respiration and reversal of the positive correlation between ROS and ΔΨmt. In contrast, an equitoxic dose of Ca caused transient depolarization, and stimulation of both respiration and H2O2 release, effects that were completely abolished when the MCU was blocked. Contrary to our expectation that mitochondrial transition ROS Spike (mTRS) would be sensitive to both Zn and Ca, only Ca suppressed it. Moreover, Zn and Ca in combination immediately depolarized the ΔΨmt, and caused transient and sustained stimulation of respiration and H2O2 release, respectively. Lastly, we uncovered and characterized an mPTP-independent Ca-induced depolarization spike that was associated with exposure to moderately elevated levels of Ca. Importantly, we showed the stimulation of ROS release associated with highly elevated but not unrealistic Ca loads was not the cause but a result of mPTP opening in the high conductance mode.Copyright © 2017 Elsevier B.V. All rights reserved.Ca loads was not the cause but a result of mPTP opening in the high conductance mode. Copyright © 2017 Elsevier B.V. All rights reserved.)
McClelland 1998 Proc Natl Acad Sci U S A + (At high altitude (HA), carbohydrate (CHO) … At high altitude (HA), carbohydrate (CHO) is thought to be the preferred fuel because of its higher yield of ATP per mole of O2. We used indirect calorimetry and D-[6-3H]glucose infusions to determine total CHO and circulatory glucose utilization during exercise in HA-acclimated and sea level (SL) rats. We hypothesized that the percent contribution of CHO to total metabolism (VO2) is determined by exercise intensity relative to an aerobic maximum (% VO2max). HA rats run under hypoxia (FIO2 = 0.12) showed a decrease in VO2max compared with SL (67.55 +/- 1.26 vs. 89.30 +/- 1.23 ml kg-1 min-1). When exercised at 60% of their respective VO2max, both groups showed the same relative use of CHO (38 +/- 3% and 38 +/- 5% of VO2, at the beginning of exercise, in HA and SL, respectively). In both HA and SL, circulatory glucose accounted for approximately 20% of VO2, the balance was provided by muscle glycogen (approximately 18% of VO2). After 20 min at a higher intensity of 80% VO2max, 54 +/- 5% (HA) and 59 +/- 4% (SL) of VO2 was accounted for by CHO. We conclude the following: (i) the relative contributions of total CHO, circulatory glucose, and muscle glycogen do not increase after HA acclimation because the O2-saving advantage of CHO is outweighed by limited CHO stores; and (ii) relative exercise intensity is the major determinant of metabolic fuel selection at HA, as well as at SL.ic fuel selection at HA, as well as at SL.)
Murray 2015 Exp Physiol + (At high-altitude barometric pressure falls … At high-altitude barometric pressure falls, challenging oxygen delivery to the tissues. Thus, whilst hypoxia is not the only physiological stress encountered at high-altitude, low arterial PO2 is a sustained feature, even after allowing adequate time for acclimatisation. Cardiac and skeletal muscle energy metabolism is altered in subjects at, or returning from, high-altitude. In the heart, energetic reserve falls, as indicated by lower phosphocreatine-to-ATP ratios. The underlying mechanism is unknown but in the hypoxic rat heart fatty acid oxidation and respiratory capacity are decreased, whilst pyruvate oxidation is also lower after sustained hypoxic exposure. In skeletal muscle, there is not a consensus. With prolonged exposure to extreme high-altitude (> 5500 m) a loss of muscle mitochondrial density is seen, but this was not observed in a simulated ascent of Everest in hypobaric chambers. At more moderate high-altitude, decreased respiratory capacity may occur without changes in mitochondrial volume density, and fat oxidation may be downregulated, though this is not seen in all studies. The underlying mechanisms, including the possible role of hypoxia-signalling pathways, remain to be resolved, particularly in light of confounding factors in the high-altitude environment. In high-altitude adapted Tibetan natives, however, there is evidence of natural selection centred around the hypoxia-inducible factor (HIF) pathway, and metabolic features in this population (e.g. low cardiac PCr/PCr, increased cardiac glucose uptake, lower muscle mitochondrial densities), share similarities with those in acclimatised lowlanders, supporting a possible role for the HIF pathway in the metabolic response of cardiac and skeletal muscle energy metabolism to high-altitude. This article is protected by copyright. All rights reserved. protected by copyright. All rights reserved.)
Yu 2023 Biochim Biophys Acta Bioenerg + (At low inner mitochondrial membrane potent … At low inner mitochondrial membrane potential (ΔΨ) oxaloacetate (OAA) accumulates in the organelles concurrently with decreased complex II-energized respiration. This is consistent with ΔΨ-dependent OAA inhibition of succinate dehydrogenase. To assess the metabolic importance of this process, we tested the hypothesis that perturbing metabolic clearance of OAA in complex II-energized mitochondria would alter O2 flux and, further, that this would occur in both ΔΨ and tissue-dependent fashion. We carried out respiratory and metabolite studies in skeletal muscle and interscapular brown adipose tissue (IBAT) directed at the effect of OAA transamination to aspartate (catalyzed by the mitochondrial form of glutamic-oxaloacetic transaminase, Got2) on complex II-energized respiration. Addition of low amounts of glutamate to succinate-energized mitochondria at low ΔΨ increased complex II (succinate)-energized respiration in muscle but had little effect in IBAT mitochondria. The transaminase inhibitor, aminooxyacetic acid, increased OAA concentrations and impaired succinate-energized respiration in muscle but not IBAT mitochondria at low but not high ΔΨ. Immunoblotting revealed that Got2 expression was far greater in muscle than IBAT mitochondria. Because we incidentally observed metabolism of OAA to pyruvate in IBAT mitochondria, more so than in muscle mitochondria, we also examined the expression of mitochondrial oxaloacetate decarboxylase (ODX). ODX was detected only in IBAT mitochondria. In summary, at low but not high ΔΨ, mitochondrial transamination clears OAA preventing loss of complex II respiration: a process far more active in muscle than IBAT mitochondria. We also provide evidence that OAA decarboxylation clears OAA to pyruvate in IBAT mitochondria.oxylation clears OAA to pyruvate in IBAT mitochondria.)
Cadenas 2006 Biochim Biophys Acta + (At low oxygen levels, mitochondrial respir … At low oxygen levels, mitochondrial respiration is controlled by the nitric oxide (NO)-cytochrome c oxidase (COX) signaling pathway, since NO is a membrane-permeant second messenger and competitive inhibitor of COX (1). It is now well established that oxygraphs, with Teflon-coated stirrer bars and other plastic materials of high oxygen solubility, yield high rates of oxygen back-diffusion into the chamber when oxygen levels decline, causing artefacts of respiratory measurements. High-resolution respirometry with the Oroboros O2k reduces such back-diffusion by at least an order of magnitude, and incorporates automatic instrumental background corrections, treating the ‘closed’ chamber essentially as an open system with oxygen transport between the aqueous phase and the system boundary (2). For measurement of NO in experimental chambers, however, the same instrumental problem of gas exchange between hydrophobic plastic materials and the aqueous medium has not been addressed, despite the high partition coefficient of NO between aqueous and organic phases (3). To address these problems, we incorporated an NO sensor (ISO-NOP, WPI) into a Hansatech oxygraph chamber and a high-resolution respirometer (O2k), for simultaneous recording of respiration and NO. The NO sensor was calibrated by addition of known concentrations of KNO2 under reducing conditions (KI/H2SO4) at 37 ºC and the response of the NO sensor in terms of accuracy, stability and reproducibility of the signal was compared between the two chambers. Measurements were taken in 1 ml (Hansatech) or 2 ml (O2k) closed chambers at 37 ºC, using their standard Teflon- or PEEK-coated stirrer bars, respectively. The titanium stopper of the O2k chamber was replaced by a polyvinylidenfluorid (PVDF) stopper, including a second inlet (2 mm diameter) for the NO sensor in addition to the capillary used for extrusion of gas bubbles and titration of chemicals. The PVDF stopper showed identical characteristics to titanium in terms of minimum back-diffusion of oxygen in aerobic-anaerobic transitions, can be cleaned with 70 % and pure ethanol, and offers increased flexibility for accommodation of various additional electrodes for multi-sensor applications. We compared the response of the NO sensor in the determination of the release of NO from a chemical source (DETA-NO) and the endogenous release from controlled intracellular NO production. We determined the inhibition of respiration caused by NO under physiological oxygen concentrations using conventional and high-resolution respirometry (2).ntrations using conventional and high-resolution respirometry (2).)
Reijne 2016 PLOS ONE + (At old age, humans generally have declinin … At old age, humans generally have declining muscle mass and increased fat deposition, which can increase the risk of developing cardiometabolic diseases. While regular physical activity postpones these age-related derangements, this is not always possible in the elderly because of disabilities or risk of injury. Whole-body vibration (WBV) training may be considered as an alternative to physical activity particularly in the frail population. To explore this possibility, we characterized whole-body and organ-specific metabolic processes in 6-month and 25-month old mice, over a period of 14 weeks of WBV versus sham training. WBV training tended to increase blood glucose turnover rates and stimulated hepatic glycogen utilization during fasting irrespective of age. WBV was effective in reducing white fat mass and hepatic triglyceride content only in old but not in young mice and these reductions were related to upregulation of hepatic mitochondrial uncoupling of metabolism (assessed by high-resolution respirometry) and increased expression of uncoupling protein 2. Because these changes occurred independent of changes in food intake and whole-body metabolic rate (assessed by indirect calorimetry), the liver-specific effects of WBV may be a primary mechanism to improve metabolic health during aging, rather than that it is a consequence of alterations in energy balance.sequence of alterations in energy balance.)
Miller 2017 PLOS ONE + (At the annual Iditarod Race, Alaskan Huski … At the annual Iditarod Race, Alaskan Huskies repeatedly run for up to 8 hours at 16 km/h to complete 1600 km. We previously demonstrated high rates of mitochondrial protein synthesis in Alaskan Huskies, which we suspected allowed rapid remodeling of mitochondrial proteins in response to energetic stress. The purpose of this study was to examine mitochondrial respiration in permeabilized skeletal muscle fibers of Alaskan Huskies in the offseason (Non-raced) and following the 1600 km Iditarod Sled Dog Race (Raced). We hypothesized that compared to Non-raced Huskies, raced Huskies that completed a 1600 km race would have greater mitochondrial respiratory capacities, and improvements in capacities of oxidative phosphorylation (OXPHOS) based on NADH-generating substrates as compared to fatty acids. Using high-resolution respirometry (HRR) we investigated the respiration of permeabilized muscle fibers from Alaskan Huskies. Maximum capacities were 254±26 pmol.s-1.mg-1 for OXPHOS (coupled, P) and 254±37 pmol.s-1.mg-1 for the electron transfer-pathway (ET-pathway; non-coupled, E). After racing respiratory capacities from NADH-linked substrates, but not fat-derived substrates increased. Finally, the OXPHOS to ET capacity ratio (P/E) increased after racing from 0.90±0.03 to 0.97±0.02. From our previous studies and the current study, we conclude that Alaskan Huskies maintain high mitochondrial protein turnover to facilitate rapid adaptation to environmental extremes and energetic challenges.urnover to facilitate rapid adaptation to environmental extremes and energetic challenges.)
Koendjbiharie 2021 FEMS Microbiol Rev + (At the junction between the glycolysis and … At the junction between the glycolysis and the tricarboxylic acid cycle-as well as various other metabolic pathways-lies the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate node (PPO-node). These three metabolites form the core of a network involving at least eleven different types of enzymes, each with numerous subtypes. Obviously, no single organism maintains each of these eleven enzymes; instead, different organisms possess different subsets in their PPO-node, which results in a remarkable degree of variation, despite connecting such deeply conserved metabolic pathways as the glycolysis and the tricarboxylic acid cycle. The PPO-node enzymes play a crucial role in cellular energetics, with most of them involved in (de)phosphorylation of nucleotide phosphates, while those responsible for malate conversion are important redox enzymes. Variations in PPO-node therefore reflect the different energetic niches that organisms can occupy. In this review, we give an overview of the biochemistry of these eleven PPO-node enzymes. We attempt to highlight the variation that exists, both in PPO-node compositions, as well as in the roles that the enzymes can have within those different settings, through various recent discoveries in both bacteria and archaea that reveal deviations from canonical functions.eveal deviations from canonical functions.)
National Academies of Sciences, Engineering, and Medicine 2023 Navigating infodemics + (At the request of the Centers for Disease … At the request of the Centers for Disease Control and Prevention (CDC), the National Academies of Sciences, Engineering, and Medicine hosted a two-day public workshop on April 10-11, 2023 to examine the history of public health infodemics, the impact of infodemics on trust in the public health enterprise, and tools and practices used to address infodemics.At the outset of the workshop, Howard Koh, Harvard T.H. Chan School of Public Health, described the term “infodemic” as the rapid spread of large amounts of sometimes conflicting or inaccurate information that can impede the ability of individuals, communities, and authorities to protect health and effectively respond in a crisis. Even a deluge of accurate information can overwhelm the public. In times of emergency, there may also be situations in which people do not have access to the information they need. In his closing remarks, Griffis called for increased understanding of how to resource institutions at all levels to reduce the harmful effects of mis- and disinformation. To this end, CDC conducts regular meetings with other federal agencies to coordinate responses to emerging misinformation. Furthermore, CDC is working to: (1) build improved misinformation monitoring and alert systems; (2) develop a more systematic approach to misinformation through the agency; (3) create, in collaboration with academic institutions, a system to increase sentinel data collection and social listening; (4) establish rapid response infrastructure to provide the public with accurate information from trusted community sources; and (5) develop tools for public health to predict the virality of vaccine misinformation. CDC continually strives to disseminate accurate information as it is needed through appropriate channels in order to empower the public to make decisions that support their health and wellbeing.s that support their health and wellbeing.)
Nickel 2018 IOC130 + (At the request of the author, this abstract is not made available online.)
Can 2018 IOC130 + (At the request of the author, this abstract is not made available online.)
Janowska 2018 IOC134 + (At the request of the author, this abstract is not made available online.)
Ganetzky 2018 IOC134 + (At the request of the author, this abstract is not made available online.)
Revenco 2019 Abstract IOC141 + (At the request of the author, this abstract is not made available online.)
Mueller 2023 Abstract IOC160 + (At the request of the author, this abstract is not made available online.)
Edman 2023 Abstract IOC160 + (At the request of the author, this abstract is not made available online.)
Rice 2023 Abstract IOC160 + (At the request of the author, this abstract is not made available online.)
Alves 2023 Abstract IOC162 + (At the request of the author, this abstract is not made available online.)
Panajatovic 2017 IOC124 + (At the request of the authors, this abstract is not made available online.)
Simon 2022 Function (Oxf) + (At-risk alcohol use is associated with mul … At-risk alcohol use is associated with multisystemic effects and end-organ injury, and significantly contributes to global health burden. Several alcohol-mediated mechanisms have been identified, with bioenergetic maladaptation gaining credence as an underlying pathophysiological mechanism contributing to cellular injury. This evidence-based review focuses on the current knowledge of alcohol-induced bioenergetic adaptations in metabolically active tissues: liver, cardiac and skeletal muscle, pancreas, and brain. Alcohol metabolism itself significantly interferes with bioenergetic pathways in tissues, particularly the liver. Alcohol decreases states of respiration in the electron transport chain, and activity and expression of respiratory complexes, with a net effect to decrease ATP content. In addition, alcohol dysregulates major metabolic pathways, including glycolysis, the tricarboxylic acid cycle, and fatty acid oxidation. These bioenergetic alterations are influenced by alcohol-mediated changes in mitochondrial morphology, biogenesis, and dynamics. The review highlights similarities and differences in bioenergetic adaptations according to tissue type, pattern of (acute vs. chronic) alcohol use, and energy substrate availability. The compromised bioenergetics synergizes with other critical pathophysiological mechanisms, including increased oxidative stress and accelerates cellular dysfunction, promoting senescence, programmed cell death, and end-organ injury.ogrammed cell death, and end-organ injury.)
Masci 2008 Biochim Biophys Acta + (Ataxia Telangiectasia (AT) patients are pa … Ataxia Telangiectasia (AT) patients are particularly sensitive to oxidative–nitrosative stress. Nitric oxide (NO) controls mitochondrial respiration via the reversible inhibition of complex IV. The mitochondrial response to NO of AT lymphoblastoid cells was investigated. Cells isolated from three patients and three intrafamilial healthy controls were selected showing within each group a normal diploid karyotype and homogeneous telomere length. Different complex IV NO-inhibition patterns were induced by varying the electron flux through the respiratory chain, using exogenous cell membrane permeable electron donors. Under conditions of high electron flux the mitochondrial NO inhibition of respiration was greater in AT than in control cells (P ≤ 0.05). This property appears peculiar to AT, and correlates well to the higher concentration of cytochrome c detected in the AT cells. This finding is discussed on the basis of the proposed mechanism of reaction of NO with complex IV. It is suggested that the peculiar response of AT mitochondria to NO stress may be relevant to the mitochondrial metabolism of AT patients.e mitochondrial metabolism of AT patients.)
Scheede-Bergdahl 2017 Can J Physiol Pharmacol + (Atherosclerosis is one of the leading caus … Atherosclerosis is one of the leading causes of morbidity and mortality in the Western world. Although the clinical manifestations of this disease are well documented, the etiology and progression remain to be fully understood. Recently, the mitochondria have been implicated in important cellular processes involved in development of atherosclerosis. Despite the link between mitochondria and atherosclerosis, early-phase mechanisms of the disease have yet to be elucidated. The aim of this project was to explore the role of mitochondria in vascular smooth muscle (VSMC) dedifferentiation. A murine ''in vitro'' model, involving organ culture of aortic tissue in serum-free media, was used. Mitochondrial function was measured by high-resolution respirometry. Proteins associated with the VSMC phenotype switch, as well as mitochondrial density, were assessed by immunoblotting. The findings show that intrinsic mitochondrial Complex I activity is significantly upregulated during VSMC dedifferentiation. Diminished coupling between phosphorylation and oxidation was also found, indicating a greater ADP:ATP ratio. This data suggests increased leak in the electron transport chain and altered mitochondrial function specifically at Complex I. This project provides important information regarding the role of mitochondria in the early atherosclerotic process and that detectable changes in mitochondrial function and expression are related to VSMC dedifferentiation.ion are related to VSMC dedifferentiation.)
Chowdhury 2010 Am J Physiol Endocrinol Metab + (Atherosclerotic cardiovascular disease is … Atherosclerotic cardiovascular disease is the leading cause of mortality in the Western world. Dysfunction of the mitochondrial respiratory chain and overproduction of reactive oxygen species (ROS) are associated with atherosclerosis and cardiovascular disease. Oxidation increases the atherogenecity of LDL. Oxidized LDL may be apoptotic or nonapoptotic for vascular endothelial cells (EC), depending on the intensity of oxidation. A previous study demonstrated that nonapoptotic oxidized LDL increased activity of mitochondrial complex I in human umbilical vein EC. The present study examined the impact of extensively oxidized LDL (eoLDL) on oxygen consumption and the activities of key enzymes in the mitochondrial respiratory chain of cultured porcine aortic EC. Oxygraphy detected that eoLDL significantly reduced oxygen consumption in various mitochondrial complexes. Treatment with eoLDL significantly decreased NADH-ubiquinone dehydrogenase (complex I), succinate cytochrome c reductase (complex II/III), ubiquinone cytochrome c reductase (complex III), and cytochrome c oxidase (complex IV) activities and the NAD+-to-NADH ratio in EC compared with mildly oxidized LDL, LDL, or vehicle. Butylated hydroxytoluene, a potent antioxidant, normalized eoLDL-induced reductions in complex I and III enzyme activity in EC. Mitochondria-associated intracellular ROS and release of ROS from EC were significantly increased after eoLDL treatment. These findings suggest that eoLDL impairs enzyme activity in mitochondrial respiratory chain complexes and increases ROS generation from mitochondria of arterial EC. Collectively, these effects could contribute to vascular injury and atherogenesis under conditions of hypercholesterolemia and oxidative stress.nditions of hypercholesterolemia and oxidative stress.)
Leo 2021 Conserv Physiol + (Atlantic herring (''Clupea harengus'') is … Atlantic herring (''Clupea harengus'') is a benthic spawner, therefore its eggs are prone to encounter different water conditions during embryonic development, with bottom waters often depleted of oxygen and enriched in CO2. Some Atlantic herring spawning grounds are predicted to be highly affected by ongoing Ocean Acidification and Warming with water temperature increasing by up to +3°C and CO2 levels reaching ca. 1000 μatm (RCP 8.5). Although many studies investigated the effects of high levels of CO2 on the embryonic development of Atlantic herring, little is known about the combination of temperature and ecologically relevant levels of CO2. In this study, we investigated the effects of Ocean Acidification and Warming on embryonic metabolic and developmental performance such as mitochondrial function, respiration, hatching success (HS) and growth in Atlantic herring from the Oslo Fjord, one of the spawning grounds predicted to be greatly affected by climate change. Fertilized eggs were incubated under combinations of two PCO2 conditions (400 μatm and 1100 μatm) and three temperatures (6, 10 and 14°C), which correspond to current and end-of-the-century conditions. We analysed HS, oxygen consumption (MO2) and mitochondrial function of embryos as well as larval length at hatch. The capacity of the electron transport system (ETS) increased with temperature, reaching a plateau at 14°C, where the contribution of Complex I to the ETS declined in favour of Complex II. This relative shift was coupled with a dramatic increase in MO2 at 14°C. HS was high under ambient spawning conditions (6-10°C), but decreased at 14°C and hatched larvae at this temperature were smaller. Elevated PCO2 increased larval malformations, indicating sub-lethal effects. These results indicate that energetic limitations due to thermally affected mitochondria and higher energy demand for maintenance occur at the expense of embryonic development and growth.mally affected mitochondria and higher energy demand for maintenance occur at the expense of embryonic development and growth.)
Leo 2018 Conserv Physiol + (Atlantic herring (Clupea harengus) is a be … Atlantic herring (Clupea harengus) is a benthic spawner, therefore its eggs are prone to encounter different water conditions during embryonic development, with bottom waters often depleted of oxygen and enriched in CO2. Some Atlantic herring spawning grounds are predicted to be highly affected by ongoing Ocean Acidification and Warming with water temperature increasing by up to +3°C and CO2 levels reaching ca. 1000 μatm (RCP 8.5). Although many studies investigated the effects of high levels of CO2 on the embryonic development of Atlantic herring, little is known about the combination of temperature and ecologically relevant levels of CO2. In this study, we investigated the effects of Ocean Acidification and Warming on embryonic metabolic and developmental performance such as mitochondrial function, respiration, hatching success (HS) and growth in Atlantic herring from the Oslo Fjord, one of the spawning grounds predicted to be greatly affected by climate change. Fertilized eggs were incubated under combinations of two PCO2 conditions (400 μatm and 1100 μatm) and three temperatures (6, 10 and 14°C), which correspond to current and end-of-the-century conditions. We analysed HS, oxygen consumption (MO2) and mitochondrial function of embryos as well as larval length at hatch. The capacity of the electron transport system (ETS) increased with temperature, reaching a plateau at 14°C, where the contribution of Complex I to the ETS declined in favour of Complex II. This relative shift was coupled with a dramatic increase in MO2 at 14°C. HS was high under ambient spawning conditions (6-10°C), but decreased at 14°C and hatched larvae at this temperature were smaller. Elevated PCO2 increased larval malformations, indicating sub-lethal effects. These results indicate that energetic limitations due to thermally affected mitochondria and higher energy demand for maintenance occur at the expense of embryonic development and growth.pense of embryonic development and growth.)
Koopman 2022 Abstract Bioblast + (Attachment of cargo molecules to lipophili … Attachment of cargo molecules to lipophilic triphenylphosphonium (TPP+) cations is a widely applied key technology for mitochondrial targeting. We previously demonstrated that the vitamin E-derived antioxidant (Trolox; 500 nM; 96 h) increases the levels of active mitochondrial Complex I (CI), the first complex of the electron transfer system (ETS), in primary human skin fibroblasts (PHSFs) of Leigh Syndrome (LS) patients with isolated CI deficiency. Primed by this finding, we here studied the cellular effects of mitochondria-targeted Trolox (MitoE10), mitochondria-targeted ubiquinone (MitoQ10) and their mitochondria-targeting moiety decylTPP (C10-TPP+). Relative to vehicle (DMSO), chronic treatment (100 nM, 96 h) with these molecules of PHSFs from a healthy subject and an LS patient with isolated CI deficiency (''NDUFS7-V122M'' mutation) did not greatly affect cell viability. Unexpectedly, this treatment significantly reduced CI levels/activity, lowered the amount of ETS supercomplexes, inhibited mitochondrial oxygen consumption, increased extracellular acidification, altered mitochondrial morphology and stimulated the levels of hydroethidine-oxidizing ROS.We conclude that the mitochondria-targeting decylTPP moiety is responsible for the observed effects and advocate that every study employing alkylTPP-mediated mitochondrial targeting should routinely include control experiments with the corresponding alkylTPP moiety. routinely include control experiments with the corresponding alkylTPP moiety.)
Poole 2020 J Physiol + (August Krogh twice won the prestigious int … August Krogh twice won the prestigious international Steegen Prize, for nitrogen metabolism (1906) and overturning the concept of active transport of gases across the pulmonary epithelium (1910). Despite this, at the beginning of 1920, the consummate experimentalist was relatively unknown worldwide and even among his own University of Copenhagen faculty. But, in early 1919, he had submitted three papers to Dr Langley, then editor of The Journal of Physiology in England. These papers coalesced anatomical observations of skeletal muscle capillary numbers with O2 diffusion theory to propose a novel active role for capillaries that explained the prodigious increase in blood-muscle O2 flux from rest to exercise. Despite his own appraisal of the first two papers as "rather dull" to his friend, the eminent Cambridge respiratory physiologist, Joseph Barcroft, Krogh believed that the third one, dealing with O2 supply and capillary regulation, was "interesting". These papers, which won Krogh an unopposed Nobel Prize for Physiology or Medicine in 1920, form the foundation for this review. They single-handedly transformed the role of capillaries from passive conduit and exchange vessels, functioning at the mercy of their upstream arterioles, into independent contractile units that were predominantly closed at rest and opened actively during muscle contractions in a process he termed 'capillary recruitment'. Herein we examine Krogh's findings and some of the experimental difficulties he faced. In particular, the boundary conditions selected for his model (e.g. heavily anaesthetized animals, negligible intramyocyte O2 partial pressure, binary open-closed capillary function) have not withstood the test of time. Subsequently, we update the reader with intervening discoveries that underpin our current understanding of muscle microcirculatory control and place a retrospectroscope on Krogh's discoveries. The perspective is presented that the imprimatur of the Nobel Prize, in this instance, may have led scientists to discount compelling evidence. Much as he and Marie Krogh demonstrated that active transport of gases across the blood-gas barrier was unnecessary in the lung, capillaries in skeletal muscle do not open and close spontaneously or actively, nor is this necessary to account for the increase in blood-muscle O2 flux during exercise. Thus, a contemporary model of capillary function features most muscle capillaries supporting blood flow at rest, and, rather than capillaries actively vasodilating from rest to exercise, increased blood-myocyte O2 flux occurs predominantly via elevating red blood cell and plasma flux in already flowing capillaries. Krogh is lauded for his brilliance as an experimentalist and for raising scientific questions that led to fertile avenues of investigation, including the study of microvascular function.uding the study of microvascular function.)
Radenkovic 2017 Biochem Pharmacol + (Auranofin is a thiol-reactive gold (I)-con … Auranofin is a thiol-reactive gold (I)-containing compound with potential asa chemotherapeutic. Auranofin has the capacity to selectively inhibit endogenous antioxidant enzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx), resulting in oxidative stress and the initiation of a pro-apoptotic cascade. The effect of Auranofin exposure on TrxR and GPx, and the potential for cellular protection through selenium supplementation was examined in the non-cancerous human cell line Swan-71. Auranofin exposure resulted in a concentration dependent differential inhibition of selenoprotein antioxidants. Significant inhibition of TrxR was observed at 20nM Auranofin with inhibition of GPx from 10µM. Significant increases in reactive oxygen species (ROS) were associated with antioxidant inhibition at Auranofin concentrations of 100nM (TrxR inhibition) and 10µM (TrxR and GPx inhibition), respectively. Evaluation of mitochondrial respiration demonstrated significant reductions in routine and maximal respiration at both 100nM and 10μM Auranofin. Auranofin treatment at concentrations of 10μM and higher concentrations resulted in a ∼68% decrease in cellular viability and was associated with elevations in pro-apoptotic markers cytochrome c flux control factor (FCFc) at concentration of 100nM and mitochondrial Bax at 10μM. The supplementation of selenium (100nM) prior to treatment had a generalized protective affect through the restoration of antioxidant activity with a significant increase in TrxR and GPx activity, a significant reduction in ROS and associated improvement in mitochondrial respiration and cellular viability (10µM ∼48% increase). Selenium supplementation reduced the FCFc at low doses of Auranofin (<10μM) however no effect was noted on either FCFc or Bax at concentrations above 10μM. The inhibition of antioxidant systems in non-cancerous cells by Auranofin is strongly dose dependent, and this inhibition can be altered by selenium exposure. Therefore, Auranofin dose and the selenium status of patients are important considerations in the therapeutic use of Auranofin as an agent of chemosensitization. Auranofin as an agent of chemosensitization.)
AussieMit 2018 Melbourne AU + (AussieMit 2018, Melbourne, Australia, 2018)
AussieMit 2020 Sydney AU + (AussieMit 2020, Sydney, Australia, 2020)
AussieMit 2022 Sydney AU + (AussieMit 2022, Sydney, Australia, 2022)
Gama Perez 2023 MiP2023 + (Authors: [[Gama Perez Pau]] … Authors: [[Gama Perez Pau]] Chronic overfeeding has a profound metabolic impact on multiple tissues. Consequently, unraveling the differential adaptations in each of them is fundamental to understand the progression of obesity-related comorbidities. In our laboratory we have tackled this issue in a model of obesity and weight loss induced by a combined nutritional and exercise intervention. This model has enabled us to identify visceral adipose tissue as the most vulnerable organ to such stress, not only by the magnitude of changes observed in the obese state but most importantly, because of the permanent alterations we observe even after the restoration of adequate weight and metabolic health. Whether this fingerprint is a distinctive trait of the visceral fat or it is affecting other depots is still unsolved, although the recognized developmental, morphological as well as functional differences among fat depots might drive a differential response.To this end, we aim to explore the subcutaneous adipose tissue behavior in our model, characterizing those significant indicators of vulnerability already identified in the visceral depot. These include linear regression models to correlate tissue mass and body weight, histological and immunohistochemical analysis to characterize the morphological remodeling of the tissue, the assessment of transcriptional changes in both tissues, as well as the impact on mitochondria through the evaluation of OXPHOS capacities and the quantification of mitochondrial DNA.This comparative analysis suggests that unlike visceral fat, the detrimental impact of chronic overfeeding is blunted in subcutaneous adipose tissue, with no apparent consequences on its metabolic plasticity. Among the important points to consider, these findings could represent a relevant concern for the study of obesity-related pathophysiology in humans since, thus far, most longitudinal studies exploring adipose tissue responses to weight fluctuations have been addressed in subcutaneous biopsies due to ethical constrains.ed in subcutaneous biopsies due to ethical constrains.)
Yardeni 2021 Proc Natl Acad Sci U S A + (Autism spectrum disorders (ASDs) are chara … Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations.y regional neurophysiological alterations.)
Kim 2018 Pflugers Arch + (Autophagy and mitophagy are important for … Autophagy and mitophagy are important for training-inducible muscle adaptations, yet it remains unclear how these systems are regulated throughout the adaptation process. Here, we studied autophagic and mitophagic flux in the skeletal muscles of Sprague-Dawley rats (300-500 g) exposed to chronic contractile activity (CCA; 3 h/day, 9 V, 10 Hz continuous, 0.1 ms pulse duration) for 1, 2, 5, and 7 days (N = 6-8/group). In order to determine the flux rates, colchicine (COL; 0.4 mg/ml/kg) was injected 48 h before tissue collection, and we evaluated differences of autophagosomal protein abundances (LC3-II and p62) between colchicine- and saline-injected animals. We confirmed that CCA resulted in mitochondrial adaptations, including improved state 3 respiration as early as day 1 in permeabilized muscle fibers, as well significant increases in mitochondrial respiratory capacity and marker proteins in IMF mitochondria by day 7. Mitophagic and autophagic flux (LC3-II and p62) were significantly decreased in skeletal muscle following 7 days of CCA. Notably, the mitophagic system seemed to be downregulated prior (day 3-5) to changes in autophagic flux (day 7), suggesting enhanced sensitivity of mitophagy compared to autophagy with chronic muscle contraction. Although we detected no significant change in the nuclear translocation of TFEB, a regulator of lysosomal biogenesis, CCA increased total TFEB protein, as well as LAMP1, in skeletal muscle. Thus, chronic muscle activity reduces mitophagy in parallel with improved mitochondrial function, and this is supported by enhanced lysosomal degradation capacity.y enhanced lysosomal degradation capacity.)
Kim 2019 Pflugers Arch + (Autophagy and mitophagy are important for … Autophagy and mitophagy are important for training-inducible muscle adaptations, yet it remains unclear how these systems are regulated throughout the adaptation process. Here, we studied autophagic and mitophagic flux in the skeletal muscles of Sprague-Dawley rats (300-500 g) exposed to chronic contractile activity (CCA; 3 h/day, 9 V, 10 Hz continuous, 0.1 ms pulse duration) for 1, 2, 5, and 7 days (N = 6-8/group). In order to determine the flux rates, colchicine (COL; 0.4 mg/ml/kg) was injected 48 h before tissue collection, and we evaluated differences of autophagosomal protein abundances (LC3-II and p62) between colchicine- and saline-injected animals. We confirmed that CCA resulted in mitochondrial adaptations, including improved state 3 respiration as early as day 1 in permeabilized muscle fibers, as well significant increases in mitochondrial respiratory capacity and marker proteins in IMF mitochondria by day 7. Mitophagic and autophagic flux (LC3-II and p62) were significantly decreased in skeletal muscle following 7 days of CCA. Notably, the mitophagic system seemed to be downregulated prior (day 3-5) to changes in autophagic flux (day 7), suggesting enhanced sensitivity of mitophagy compared to autophagy with chronic muscle contraction. Although we detected no significant change in the nuclear translocation of TFEB, a regulator of lysosomal biogenesis, CCA increased total TFEB protein, as well as LAMP1, in skeletal muscle. Thus, chronic muscle activity reduces mitophagy in parallel with improved mitochondrial function, and this is supported by enhanced lysosomal degradation capacity.y enhanced lysosomal degradation capacity.)
Dutta 2013 Autophagy + (Autophagy is a cellular self-digestion pro … Autophagy is a cellular self-digestion process that mediates protein quality control and serves to protect against neurodegenerative disorders, infections, inflammatory diseases and cancer. Current evidence suggests that autophagy can selectively remove damaged organelles such as the mitochondria. Mitochondria-induced oxidative stress has been shown to play a major role in a wide range of pathologies in several organs, including the heart. Few studies have investigated whether enhanced autophagy can offer protection against mitochondrially-generated oxidative stress. We induced mitochondrial stress in cardiomyocytes using antimycin A (Ama), which increased mitochondrial superoxide generation, decreased mitochondrial membrane potential and depressed cellular respiration. In addition, Ama augmented nuclear DNA oxidation and cell death in cardiomyocytes. Interestingly, although oxidative stress has been proposed to induce autophagy, treatment with Ama did not result in stimulation of autophagy or mitophagy in cardiomyocytes. Our results showed that the MTOR inhibitor rapamycin induced autophagy, promoted mitochondrial clearance and protected cardiomyocytes from the cytotoxic effects of Ama, as assessed by apoptotic marker activation and viability assays in both mouse atrial HL-1 cardiomyocytes and human ventricular AC16 cells. Importantly, rapamycin improved mitochondrial function, as determined by cellular respiration, mitochondrial membrane potential and morphology analysis. Furthermore, autophagy induction by rapamycin suppressed the accumulation of ubiquitinylated proteins induced by Ama. Inhibition of rapamycin-induced autophagy by pharmacological or genetic interventions attenuated the cytoprotective effects of rapamycin against Ama. We propose that rapamycin offers cytoprotection against oxidative stress by a combined approach of removing dysfunctional mitochondria as well as by degrading damaged, ubiquitinated proteins. We conclude that autophagy induction by rapamycin could be utilized as a potential therapeutic strategy against oxidative stress-mediated damage in cardiomyocytes. stress-mediated damage in cardiomyocytes.)
Leduc-Gaudet 2023 Nat Commun + (Autophagy is a critical process in the reg … Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity ''in vivo''. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.gulator of muscle autophagy and integrity.)
De Castro IP 2013 Cell Death Dis + (Autophagy is a critical regulator of organ … Autophagy is a critical regulator of organellar homeostasis, particularly of mitochondria. Upon the loss of membrane potential, dysfunctional mitochondria are selectively removed by autophagy through recruitment of the E3 ligase Parkin by the PTEN-induced kinase 1 (PINK1) and subsequent ubiquitination of mitochondrial membrane proteins. Mammalian sequestrome-1 (p62/SQSTM1) is an autophagy adaptor, which has been proposed to shuttle ubiquitinated cargo for autophagic degradation downstream of Parkin. Here, we show that loss of ''ref(2)P'', the ''Drosophila'' orthologue of mammalian ''P62'', results in abnormalities, including mitochondrial defects and an accumulation of mitochondrial DNA with heteroplasmic mutations, correlated with locomotor defects. Furthermore, we show that expression of Ref(2)P is able to ameliorate the defects caused by loss of Pink1 and that this depends on the presence of functional Parkin. Finally, we show that both the PB1 and UBA domains of Ref(2)P are crucial for mitochondrial clustering. We conclude that Ref(2)P is a crucial downstream effector of a pathway involving Pink1 and Parkin and is responsible for the maintenance of a viable pool of cellular mitochondria by promoting their aggregation and autophagic clearance.heir aggregation and autophagic clearance.)
Setz 2018 Hear Res + (Autophagy is a highly evolutionary conserv … Autophagy is a highly evolutionary conserved quality control defense mechanism within cells, which has also been implicated in cell death processes. In the mammalian inner ear, autophagy has been shown to play a role during early morphogenesis as well as in adult cochlear hair cells exposed to ototoxic insults. Mitophagy, a selective autophagic cell process targeting mitochondria, hasn't been studied in the inner ear so far. On this work, we searched for molecular indicators of mitophagy within House Ear Institute-Organ of Corti-1 (HEI-OC1) cells as well as in the organ of Corti (OC). We first tested for the expression of ''Pink1''/''Park2'' mRNA in 5-day-old C57BL/6 mice's cochleae using RT-PCR. We focused on the induction of mitophagy in HEI-OC1 cells as well as in the OC and investigated a possible mitophagic potential of the aminoglycoside agent gentamicin. The induction of mitophagy in HEI-OC1 cells was detected by objectivizing the translocation of fluorescence-tagged LC3 to mitochondria using confocal microscopy after a 6-h incubation with a well-described mitochondrial uncoupler and mitophagy-inducing agent: carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Incubation with gentamicin generated no mitochondrial translocation of LC3. Protein levels of COXIV, Atg5/12 and LC3 were evaluated by an immunoblot analysis after a 24-h CCCP treatment as well as gentamicin. We demonstrated mitophagy after CCCP exposure in HEI-OC1 cells by showing a downregulation of COXIV. A downregulation of COXIV could also be visualized in the OC after CCCP. A significant oxygen consumption rate (OCR) changed in cells treated with CCCP as well as significant morphological changes of mitochondria by electron microscopy (EM) strengthen this assumption. Gentamicin exposure generated no impact on OCR or mitochondrial morphological changes by EM. Finally, we demonstrated changes in the expression of Atg12 and LC3 proteins in both the OC and HEI-OC1 cells after CCCP exposure but not after gentamicin. Our data indicate that gentamicin had no impact in the activation of mitophagy-neither in the HEI-OC1 cell line nor in the OC. Therefore, we speculate that mitophagic-independent mechanisms may underly aminoglycoside ototoxicity.ms may underly aminoglycoside ototoxicity.)
Kataura 2022 Dev Cell + (Autophagy is an essential catabolic proces … Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components. Loss of autophagy in age-related human pathologies contributes to tissue degeneration through a poorly understood mechanism. Here, we identify an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD) levels, which are critical for cell survival. In respiring mouse fibroblasts with autophagy deficiency, loss of mitochondrial quality control was found to trigger hyperactivation of stress responses mediated by NADases of PARP and Sirtuin families. Uncontrolled depletion of the NAD(H) pool by these enzymes ultimately contributed to mitochondrial membrane depolarization and cell death. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient yeast, mouse fibroblasts, and human neurons. Our study provides a mechanistic link between autophagy and NAD metabolism and identifies targets for interventions in human diseases associated with autophagic, lysosomal, and mitochondrial dysfunction. lysosomal, and mitochondrial dysfunction.)
Wilson 2023 Trends Cell Biol + (Autophagy is an intracellular degradation … Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD+-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.e-related disease and promoting longevity.)
Ljubojevic-Holzer 2021 Cardiovasc Res + (Autophagy protects against the development … Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure.RT-qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5-/-). Before manifesting cardiac dysfunction, Atg5-/- mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5-/- cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5-/- cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload.Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.ed impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.)
Morselli 2011 J Cell Biol + (Autophagy protects organelles, cells, and … Autophagy protects organelles, cells, and organisms against several stress conditions. Induction of autophagy by resveratrol requires the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1). In this paper, we show that the acetylase inhibitor spermidine stimulates autophagy independent of SIRT1 in human and yeast cells as well as in nematodes. Although resveratrol and spermidine ignite autophagy through distinct mechanisms, these compounds stimulate convergent pathways that culminate in concordant modifications of the acetylproteome. Both agents favor convergent deacetylation and acetylation reactions in the cytosol and in the nucleus, respectively. Both resveratrol and spermidine were able to induce autophagy in cytoplasts (enucleated cells). Moreover, a cytoplasm-restricted mutant of SIRT1 could stimulate autophagy, suggesting that cytoplasmic deacetylation reactions dictate the autophagic cascade. At doses at which neither resveratrol nor spermidine stimulated autophagy alone, these agents synergistically induced autophagy. Altogether, these data underscore the importance of an autophagy regulatory network of antagonistic deacetylases and acetylases that can be pharmacologically manipulated.that can be pharmacologically manipulated.)
Van Bergen 2011 PLoS One + (Autosomal Dominant Optic Atrophy (ADOA) is … Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies.or preventing vision loss in optic neuropathies.)
Lesage 2016 Am J Hum Genet + (Autosomal-recessive early-onset parkinsoni … Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.shed by Elsevier Inc. All rights reserved.)
Angebault 2015 Am J Hum Genet + (Autosomal-recessive optic neuropathies are … Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in ''TMEM126A'' and ''ACO2'' are known. In four families with early-onset recessive optic neuropathy, we identified mutations in ''RTN4IP1'', which encodes a mitochondrial ubiquinol oxydo-reductase. ''RTN4IP1'' is a partner of ''RTN4'' (also known as NOGO), and its ortholog Rad8 in ''C. elegans'' is involved in UV light response. Analysis of fibroblasts from affected individuals with a ''RTN4IP1'' mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites ''in vitro'' and the eye size, neuro-retinal development, and swimming behavior in zebrafish ''in vivo''. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking ''RTN4IP1'' functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation.and dendrite growth during eye maturation.)
D'Souza 2018 J Lipid Res + (Autotaxin (ATX) is an adipokine that gener … Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX+/-) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX+/- mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS-fed ATX+/- mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.directly impairs skeletal muscle insulin signaling and mitochondrial function.)
Albertini 2012 Aging (Albany NY) + (Availability of methionine is known to mod … Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents. However, the underlying mechanisms are incompletely understood. In eukaryotic cells, methionine can be converted to cysteine through the reverse transsulfuration pathway thereby modulating intracellular methionine availability. Whereas previous results obtained in yeast and fruit flies suggest that alterations in the reverse transsulfuration pathway modulate the rate of aging, it is not known whether this function is conserved in evolution. Here we show that depletion of cystathionine beta synthase (CBS), a rate limiting enzyme in the reverse transsulfuration pathway, induces premature senescence in human endothelial cells. We found that CBS depletion induces mild mitochondrial dysfunction and increases the sensitivity of endothelial cells to homocysteine, a known inducer of endothelial cell senescence and an established risk factor for vascular disease. Our finding that CBS deficiency induces endothelial cell senescence ''in vitro'', involving both mitochondrial dysfunction and increased susceptibility of the cells to homocysteine, suggests a new mechanism linking CBS deficiency to vascular aging and disease. deficiency to vascular aging and disease.)
Ravera 2018 Biol Cell + (BACKGROUND INFORMATION: Energy demand in h … BACKGROUND INFORMATION: Energy demand in human platelets is very high, to carry out their functions. As for most human cells, the aerobic metabolism represents the primary energy source in platelets, even though mitochondria are negligibly represented. Following the hypothesis that other structures could be involved in chemical energy production, in this work, we have investigated the functional expression of an extramitochondrial aerobic metabolism in platelets.RESULTS: Oximetric and luminometric analyses showed that platelets consume large amounts of oxygen and produce ATP in the presence of common respiring substrates, such as pyruvate + malate or succinate, although morphological electron microscopy analysis showed that these contain few mitochondria. However, evaluation of the anaerobic glycolytic metabolism showed that only 13% of consumed glucose was converted to lactate. Interestingly, the highest OXPHOS activity was observed in the presence of NADH, not a readily permeant respiring substrate for mitochondria. Also, oxygen consumption and ATP synthesis fuelled by NADH were not affected by atractyloside, an inhibitor of the adenine nucleotide translocase, suggesting that these processes may not be ascribed to mitochondria. Functional data were confirmed by immunofluorescence microscopy and Western blot analyses, showing a consistent expression of the β subunit of F1 Fo -ATP synthase and COXII, a subunit of Complex IV, but a low signal of translocase of the inner mitochondrial membrane (a protein not involved in OXPHOS metabolism). Interestingly, the NADH-stimulated oxygen consumption and ATP synthesis increased in the presence of the physiological platelets agonists, thrombin or collagen.CONCLUSIONS: Data suggest that in platelets, aerobic energy production is mainly driven by an extramitochondrial OXPHOS machinery, originated inside the megakaryocyte, and that this metabolism plays a pivotal role in platelet activation.SIGNIFICANCE: This work represents a further example of the existence of an extramitochondrial aerobic metabolism, which can contribute to the cellular energy balance.contribute to the cellular energy balance.)
Regueira 2009 Liver Int + (BACKGROUND/AIMS: Genes encoding for some o … BACKGROUND/AIMS:Genes encoding for some of the mitochondrial proteins are under the control of the transcriptional factor hypoxia inducible factor-1 alpha (HIF-1 alpha), which can accumulate under normoxic conditions in inflammatory states. The aim of this study was to evaluate the effects of cobalt chloride (CoCl2, a hypoxia mimicking agent), tumour necrosis factor-alpha (TNF-alpha) and toll-like receptor (TLR) -2, -3 and -4 agonists on HIF-1 alpha accumulation, and further on HIF-1 alpha-mediated modulation of mitochondrial respiration in cultured human hepatocytes.METHODS:The human hepatoma cell line HepG2 was used in this study. Cells were treated with CoCl2, TNF-alpha and TLR-2, -3 and -4 agonists. HIF-1 alpha was determined by Western blotting and mitochondrial respiration in stimulated cells by high-resolution respirometry.RESULTS:CoCl2, TNF-alpha and TLR agonists induced the expression of HIF-1 alpha in a time-dependent fashion. TNF-alpha and CoCl2, but not TLR agonists, induced a reduction in complex I-, II- and IV-dependent mitochondrial oxygen consumption. TNF-alpha-associated reduction of cellular oxygen consumption was abolished through inhibition of HIF-1 alpha activity by chetomin (CTM). Pretreatment with cyclosporine A prevented CoCl2-induced reduction of complex I- and II-dependent mitochondrial oxygen consumption and TNF-alpha-induced reduction of complex-I-dependent respiration, implicating the involvement of the mitochondrial permeability transition pore openings. TNF-alpha and TLR-2, -3 and -4 agonists induced the expression of vascular endothelial growth factor, which was partially abolished by the blockage of HIF-1 alpha with CTM.CONCLUSIONS:The data suggest that HIF-1 alpha modulates mitochondrial respiration during CoCl2 and TNF-alpha stimulation, whereas it has no effect when induced with TLR-2, -3 and -4 agonists.>2 and TNF-alpha stimulation, whereas it has no effect when induced with TLR-2, -3 and -4 agonists.)
Escribano-Lopez 2019 Cell Physiol Biochem + (BACKGROUND/AIMS: Mitochondria-targeted ant … BACKGROUND/AIMS:Mitochondria-targeted antioxidants such as mitoquinone (MitoQ) have demonstrated protective effects against oxidative damage in several diseases. The increase in reactive oxygen species (ROS) production during glucose metabolism in β cells can be exacerbated under hyperglycaemic conditions such as type 2 diabetes (T2D), thus contributing to β cell function impairment. In the present work, we aimed to evaluate the effect of MitoQ on insulin secretion, oxidative stress, endoplasmic reticulum (ER) stress and nuclear factor kappa B (NFκB) signalling in a pancreatic β cell line under normoglycaemic (NG, 11.1 mM glucose), hyperglycaemic (HG, 25 mM glucose) and lipidic (palmitic acid (PA), 0.5mM) conditions.METHODS:We incubated the pancreatic β cell line INS-1E with or without MitoQ (0.5µM) under NG, HG and PA conditions. We then assessed the following parameters: glucose-induced insulin secretion, O₂ consumption (with a Clark-type electrode); mitochondrial function, oxidative stress parameters and calcium levels (by fluorescence microscopy); ER stress markers and NFκB-p65 protein levels (by western blotting).RESULTS:MitoQ increased insulin secretion and prevented the enhancement of ROS production and O₂ consumption and decrease in GSH levels that are characteristic under HG conditions. MitoQ also reduced protein levels of ER stress markers (GRP78 and P-eIF2α) and the proinflammatory nuclear transcription factor NFκB-p65, both of which increased under HG. MitoQ did not significantly alter ER stress markers under lipidic conditions.CONCLUSION:Our findings suggest that treatment with MitoQ modulates mitochondrial function, which in turn ameliorates endoplasmic reticulum stress and NFκB activation, thereby representing potential benefits for pancreatic β cell function.l benefits for pancreatic β cell function.)
Johnson 2016 Transfusion + (BACKGROUND: Alternatives to room temperat … BACKGROUND:Alternatives to room temperature storage of platelets (PLTs) may be beneficial to extend the limited shelf life and support transfusion logistics in rural and military areas. The aim of this study was to assess the morphologic, metabolic, and functional aspects of PLTs stored at room temperature or in refrigerated conditions or cryopreserved.STUDY DESIGN AND METHODS:A three-arm pool-and-split study was carried out using buffy coat-derived PLTs stored in 30% plasma/70% SSP+. The three matched treatment arms were room temperature stored (20-24°C), cold-stored (2-6°C), and cryopreserved (-80°C with dimethyl sulfoxide). Liquid-stored PLTs were tested over a 21-day period, while cryopreserved PLTs were examined immediately after thawing and after 6 and 24 hours of storage at room temperature.RESULTS:Cold-stored and cryopreserved PLTs underwent a significant shape change, although the cryopreserved PLTs appeared to recover from this during subsequent storage. Glycolytic metabolism was reduced in cold-stored PLTs, but accelerated in cryopreserved PLTs, while oxidative phosphorylation was negatively affected by both storage conditions. PLT aggregation was potentiated by cold storage and diminished by cryopreservation in comparison to room temperature-stored PLTs. Cold storage and cryopreservation resulted in faster clot formation (R-time; thromboelastography), which was associated with an increase in microparticles.CONCLUSION:Cold storage and cryopreservation of PLTs led to morphologic and metabolic changes. However, storage under these conditions appears to maintain or even enhance certain aspects of in vitro PLT function. certain aspects of in vitro PLT function.)
Johnson 2014 Transfusion + (BACKGROUND: Cryopreservation of platelets … BACKGROUND:Cryopreservation of platelets (PLTs) at -80°C with dimethyl sulfoxide (DMSO) can extend the shelf life from 5 days to 2 years. Cryopreserved PLTs are reported to have a greater in vivo hemostatic effect than liquid-stored PLTs. As such, the aim of this study was to understand the mechanisms responsible for the hemostatic potential of cryopreserved PLTs and the contribution of the reconstitution solution to this activity.STUDY DESIGN AND METHODS:DMSO (5% final concentration) was added to buffy coat-derived PLTs, followed by prefreeze removal of DMSO and storage at -80°C. Cryopreserved PLTs (n=8 per group) were thawed at 37°C, reconstituted with either 1 unit of thawed frozen plasma or PLT additive solution (PAS-G). In vitro assays were performed before freezing and after thawing to assess the hemostatic activity of PLTs.RESULTS:Cryopreserved PLTs expressed high levels of phosphatidylserine and contained significantly more phosphatidylserine-positive PLT microparticles than liquid-stored PLTs. This was accompanied by a significant decrease in the time to clot formation and clot strength, as measured by thromboelastography. The supernatant from cryopreserved PLTs was sufficient to reduce the phosphatidylserine-dependent clotting time and increase the thrombin generation potential. Overall, plasma-reconstituted cryopreserved PLTs were more procoagulant than those reconstituted in PAS-G.CONCLUSION:PLT cryopreservation results in the generation of phosphatidylserine-expressing PLT microparticles which contribute to the hemostatic activity. Understanding the hemostatic activity of these components may assist in extending the use of these specialized components beyond military applications.d components beyond military applications.)
Angiulli 2015 Biochim Biophys Acta + (BACKGROUND: ''Leishmania infantum'' is a p … BACKGROUND:''Leishmania infantum'' is a protozoan of the trypanosomatid family causing ''visceral leishmaniasis''. ''Leishmania'' parasites are transmitted by the bite of phlebotomine sand flies to the human host and are phagocyted by macrophages. The parasites synthesize N1-N8-bis(glutationyl)-spermidine (trypanothione, TS2), which furnishes electrons to the tryparedoxin-tryparedoxin peroxidase couple to reduce the reactive oxygen species produced by macrophages. Trypanothione is kept reduced by trypanothione reductase (TR), a FAD-containing enzyme essential for parasite survival.METHODS:The enzymatic activity has been studied by stopped-flow, absorption spectroscopy, and amperometric measurements.RESULTS:The study reported here demonstrates that the steady-state parameters change as a function of the order of substrates addition to the TR-containing solution. In particular, when the reaction is carried out by adding NADPH to a solution containing the enzyme and trypanothione, the KM for NADPH decreases six times compared to the value obtained by adding TS2 as last reagent to start the reaction (1.9 vs. 12 μM). More importantly, we demonstrate that TR is able to catalyze the oxidation of NADPH also in the absence of trypanothione. Thus, TR catalyzes the reduction of O2 to water through the sequential formation of C(4a)-(hydro)peroxyflavin and sulfenic acid intermediates. This NADPH:O2 oxidoreductase activity is shared by ''Saccharomyces cerevisiae'' glutathione reductase (GR).CONCLUSIONS:TR and GR, in the absence of their physiological substrates, may catalyze the electron transfer reaction from NADPH to molecular oxygen to yield water.GENERAL SIGNIFICANCE:TR and GR are promiscuous enzymes.d water. GENERAL SIGNIFICANCE: TR and GR are promiscuous enzymes.)
Montaigne 2014 Circulation + (BACKGROUND: -Obesity and diabetes mellitus … BACKGROUND:-Obesity and diabetes mellitus (DM) are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance and DM on intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy.METHODS AND RESULTS:-Right atrial myocardium was obtained from 141 consecutive patients, presenting no sign of cardiomyopathy. We investigated (i) ex vivo isometric contraction (ii) mitochondrial respiration and calcium retention capacity (iii) respiratory chain complex activities and oxidative stress status. DM was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction and increased myocardial oxidative stress, irrespective of weight status. By contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated haemoglobin (HbA1C), but neither body mass index nor the insulin resistance index HOMA-IR, was independently associated with cardiac mitochondrial function. Furthermore, DM was associated with cardiac mitochondrial network fragmentation and significant decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to HbA1C.CONCLUSIONS:-Worsening of intrinsic myocardial contraction in the transition from obesity to DM is likely related to worsening of cardiac mitochondrial function, since impaired mitochondrial function and dynamics, as well as contractile dysfunction are observed in diabetic patients but not in "metabolically healthy" obese patients at early stage in insulin resistance.ents at early stage in insulin resistance.)
Syrjanen 2015 Front Zool + (BACKGROUND: Carbonic anhydrases (CAs, EC 4 … BACKGROUND:Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous enzymes that catalyze the reversible hydration reaction of carbon dioxide. CAs are present as six structurally divergent enzyme families: α, β, γ, δ, ζ and η. β-CAs have a wide distribution across different species including invertebrates. Previously, we showed that Drosophila melanogaster β-CA is a highly active mitochondrial enzyme. In this study, we investigated the function of Drosophila β-CA by silencing the expression of the β-CA gene using UAS/GAL4-based RNA interference (RNAi) in Drosophila in vivo.RESULTS:Crossing β-CA RNAi lines over ubiquitous Actin driver flies did not produce any viable progeny, indicating that β-CA expression is required for fly development. RNAi silencing of β-CA ubiquitously in adult flies did not affect their survival rate or function of mitochondrial electron transport chain. Importantly, β-CA RNAi led to impaired reproduction. All β-CA knockdown females were sterile, and produced few or no eggs. Whole ovaries of knockdown females looked normal but upon cadherin staining, there was an apparent functional defect in migration of border cells, which are considered essential for normal fertilization.CONCLUSIONS:These results indicate that although Drosophila β-CA is dispensable for survival of adult flies, it is essential for female fertility.ies, it is essential for female fertility.)
Jackson 2014 J Med Genet + (BACKGROUND: Defects of the mitochondrial r … BACKGROUND:Defects of the mitochondrial respiratory chain complex II (succinate dehydrogenase (SDH) complex) are extremely rare. Of the four nuclear encoded proteins composing complex II, only mutations in the 70 kDa flavoprotein (SDHA) and the recently identified complex II assembly factor (SDHAF1) have been found to be causative for mitochondrial respiratory chain diseases. Mutations in the other three subunits (SDHB, SDHC, SDHD) and the second assembly factor (SDHAF2) have so far only been associated with hereditary paragangliomas and phaeochromocytomas. Recessive germline mutations in SDHB have recently been associated with complex II deficiency and leukodystrophy in one patient.METHODS AND RESULTS:We present the clinical and molecular investigations of the first patient with biochemical evidence of a severe isolated complex II deficiency due to compound heterozygous SDHD gene mutations. The patient presented with early progressive encephalomyopathy due to compound heterozygous p.E69 K and p.*164Lext*3 SDHD mutations. Native polyacrylamide gel electrophoresis and western blotting demonstrated an impaired complex II assembly. Complementation of a patient cell line additionally supported the pathogenicity of the novel identified mutations in SDHD.CONCLUSIONS:This report describes the first case of isolated complex II deficiency due to recessive SDHD germline mutations. We therefore recommend screening for all SDH genes in isolated complex II deficiencies. It further emphasises the importance of appropriate genetic counselling to the family with regard to SDHD mutations and their role in tumorigenesis.mutations and their role in tumorigenesis.)
Errea 2015 J Neuroinflammation + (BACKGROUND: In brain inflammatory diseases … BACKGROUND:In brain inflammatory diseases, axonal damage is one of the most critical steps in the cascade that leads to permanent disability. Thus, identifying the initial events triggered by inflammation or oxidative stress that provoke axonal damage is critical for the development of neuroprotective therapies. Energy depletion due to mitochondrial dysfunction has been postulated as an important step in the damage of axons. This prompted us to study the effects of acute inflammation and oxidative stress on the morphology, transport, and function of mitochondria in axons.METHODS:Mouse cerebellar slice cultures were challenged with either lipopolysaccharide (LPS) or hydrogen peroxide (H2O2) ex vivo for 24 h. Axonal mitochondrial morphology was evaluated by transmission electron microscopy (TEM) and mitochondrial transportation by time-lapse imaging. In addition, mitochondrial function in the cerebellar slice cultures was analyzed through high-resolution respirometry assays and quantification of adenosine triphosphate (ATP) production.RESULTS:Both conditions promoted an increase in the size and complexity of axonal mitochondria evident in electron microscopy images, suggesting a compensatory response. Such compensation was reflected at the tissue level as increased respiratory activity of complexes I and IV and as a transient increase in ATP production in response to acute inflammation. Notably, time-lapse microscopy indicated that mitochondrial transport (mean velocity) was severely impaired in axons, increasing the proportion of stationary mitochondria in axons after LPS challenge. Indeed, the two challenges used produced different effects: inflammation mostly reducing retrograde transport and oxidative stress slightly enhancing retrograde transportation.CONCLUSIONS:Neuroinflammation acutely impairs axonal mitochondrial transportation, which would promote an inappropriate delivery of energy throughout axons and, by this way, contribute to axonal damage. Thus, preserving axonal mitochondrial transport might represent a promising avenue to exploit as a therapeutic target for neuroprotection in brain inflammatory diseases like multiple sclerosis.ammatory diseases like multiple sclerosis.)
Vijgen 2013 Surg Obes Relat Dis + (BACKGROUND: Obesity and type 2 diabetes ar … BACKGROUND:Obesity and type 2 diabetes are associated with impaired skeletal muscle mitochondrial metabolism. As an intrinsic characteristic of an individual, skeletal muscle mitochondrial dysfunction could be a risk factor for weight gain and obesity-associated co-morbidities, such as type 2 diabetes. On the other hand, impaired skeletal muscle metabolism could be a consequence of obesity. We hypothesize that marked weight loss after bariatric surgery recovers skeletal muscle mitochondrial function.METHODS:Skeletal muscle mitochondrial function as assessed by high-resolution respirometry was measured in 8 morbidly obese patients (body mass index [BMI], 41.3±4.7 kg/m2; body fat, 48.3%±5.2%) before and 1 year after bariatric surgery (mean weight loss: 35.0±8.6 kg). The results were compared with a lean (BMI 22.8±1.1 kg/m2; body fat, 15.6%±4.7%) and obese (BMI 33.5±4.2 kg/m2; body fat, 34.1%±6.3%) control group.RESULTS:Before surgery, adenosine diphosphate (ADP)-stimulated (state 3) respiration on glutamate/succinate was decreased compared with lean patients (9.5±2.4 versus 15.6±4.4 O2 flux/mtDNA; P<.05). One year after surgery, mitochondrial function was comparable to that of lean controls (after weight loss, 12.3±5.5; lean, 15.6±4.4 O2 flux/mtDNA). In addition, we observed an increased state 3 respiration on a lipid substrate after weight loss (10.0±3.2 versus 14.0±6.6 O2 flux/mtDNA; P< .05).CONCLUSIONS:We conclude that impaired skeletal muscle mitochondrial function is a consequence of obesity that recovers after marked weight loss. obesity that recovers after marked weight loss.)
Leo 2017 Front Zool + (BACKGROUND: Ocean acidification and warmin … BACKGROUND:Ocean acidification and warming are happening fast in the Arctic but little is known about the effects of ocean acidification and warming on the physiological performance and survival of Arctic fish.RESULTS:In this study we investigated the metabolic background of performance through analyses of cardiac mitochondrial function in response to control and elevated water temperatures and PCO2 of two gadoid fish species, Polar cod (Boreogadus saida), an endemic Arctic species, and Atlantic cod (Gadus morhua), which is a temperate to cold eurytherm and currently expanding into Arctic waters in the wake of ocean warming. We studied their responses to the above-mentioned drivers and their acclimation potential through analysing the cardiac mitochondrial function in permeabilised cardiac muscle fibres after 4 months of incubation at different temperatures (Polar cod: 0, 3, 6, 8 °C and Atlantic cod: 3, 8, 12, 16 °C), combined with exposure to present (400μatm) and year 2100 (1170μatm) levels of CO2. OXPHOS, proton leak and ATP production efficiency in Polar cod were similar in the groups acclimated at 400μatm and 1170μatm of CO2, while incubation at 8 °C evoked increased proton leak resulting in decreased ATP production efficiency and decreased Complex IV capacity. In contrast, OXPHOS of Atlantic cod increased with temperature without compromising the ATP production efficiency, whereas the combination of high temperature and high PCO2 depressed OXPHOS and ATP production efficiency.CONCLUSIONS:Polar cod mitochondrial efficiency decreased at 8 °C while Atlantic cod mitochondria were more resilient to elevated temperature; however, this resilience was constrained by high PCO2. In line with its lower habitat temperature and higher degree of stenothermy, Polar cod has a lower acclimation potential to warming than Atlantic cod.on potential to warming than Atlantic cod.)
Bosy-Westphal 2004 Int J Obes Relat Metab Disord + (BACKGROUND: In normal-weight subjects, r … BACKGROUND: In normal-weight subjects, resting energy expenditure (REE) can be accurately calculated from organ and tissue masses applying constant organ-specific metabolic rates. This approach allows a precise correction for between-subjects variation in REE, explained by body composition. Since a decrease in organ metabolic rate with increasing organ mass has been deduced from interspecies comparison including human studies, the validity of the organ- and tissue-specific REE calculation remains to be proved over a wider range of fat-free mass (FFM).DESIGN: In a cross-sectional study on 57 healthy adults (35 females and 22 males, 19-43 y; 14 underweight, 25 intermediate weight and 18 obese), magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) were used to assess the masses of brain, internal organs, skeletal muscle (MM), bone and adipose tissue. REE was measured by indirect calorimetry (REEm) and calculated from detailed organ size determination by MRI and DXA (REEc1), or in a simplified approach exclusively from DXA (REEc2).RESULTS: We found a high agreement between REEm and REEc1 over the whole range of FFM (28-86 kg). REE prediction errors were -17 +/- 505, -145 +/- 514 and -141 +/- 1058 kJ/day in intermediate weight, underweight and obese subjects, respectively (n.s.). Regressing REEm on FFM resulted in a significant positive intercept of 1.6 MJ/day that could be reduced to 0.5 MJ/day by adjusting FFM for the proportion of MM/organ mass. In a multiple regression analysis, MM and liver mass explained 81% of the variance in REEm. DXA-derived REE prediction showed a good agreement with measured values (mean values for REEm and REEc2 were 5.72 +/- 1.87 and 5.82 +/- 1.51 MJ/day; difference n.s.).CONCLUSION: Detailed analysis of metabolically active components of FFM allows REE prediction over a wide range of FFM. The data provide indirect evidence for a view that, for practical purposes within humans, the specific metabolic rate is constant with increasing organ mass. Nonlinearity of REE on FFM was partly explained by FFM composition. A simplified REE prediction algorithm from regional DXA measurements has to be validated in future studies.nts has to be validated in future studies.)
Haugen 2003 Am J Clin Nutr + (BACKGROUND: The necessity of a 12-h fast … BACKGROUND: The necessity of a 12-h fast before resting metabolic rate (RMR) is measured is often a barrier to measuring RMR.OBJECTIVE: We compared RMR measurements obtained in the morning and afternoon and across repeated days to elucidate the magnitude and sources of variability.DESIGN: Healthy men (n = 12) and women (n = 25) aged 21-67 y, with body mass indexes (in kg/m(2)) ranging from 17 to 34 and body fat ranging from 6% to 54%, completed 4 RMR measurements. RMR measurements were made in the morning (after a 12-h fast and 12 h postexercise) and in the afternoon (after a 4-h fast and 12 h postexercise) on 2 separate days with the ventilated-hood technique. Body composition was assessed by dual-energy X-ray absorptiometry.RESULTS: Mean (+/- SE) afternoon RMR was significantly higher than morning RMR on both visit 1 (1593.5 +/- 35.6 compared with 1508.0 +/- 31.5 kcal/d; P = 0.001) and visit 2 (1602 +/- 29.3 compared with 1511.4 +/- 35.9 kcal/d; P = 0.001). The 2 morning measurements (r = 0.93) and the 2 afternoon measurements (r = 0.93) were highly correlated, and no significant differences between measurements were observed. The mean difference between the morning and afternoon measurements was 99.0 +/- 35.8 kcal/d (6%).CONCLUSIONS: Repeated morning and evening measurements of RMR were stable and highly correlated. Day-to-day measurements of RMR were not significantly different. RMR measured in the afternoon after a 4-h fast and exercise was approximately 100 kcal/d higher than RMR measured in the morning.d higher than RMR measured in the morning.)
Sabia 2009 Am J Clin Nutr + (BACKGROUND: The extent to which cognition … BACKGROUND: The extent to which cognition in late midlife is influenced by lifetime obesity is unclear.OBJECTIVE: We examined the association between body mass index (BMI) over the adult life course and cognition in late midlife and assessed the cumulative effects of obesity and underweight.DESIGN: Data from the Whitehall II Study were examined. BMI at 25 y (early adulthood) was self-reported at phase 1 and was measured in early midlife (mean age = 44 y; phase 1) and in late midlife (mean age = 61 y; phase 7). Cognition (''n'' = 5131) was assessed in late midlife (phase 7) by using the Mini-Mental State Examination and tests of memory and executive function, all of which were standardized to ''T'' scores (mean +/- SD: 50 +/- 10).RESULTS: Both underweight and obesity were associated with lower cognition in late midlife and with early adulthood, early midlife, and late midlife measures of BMI. Being obese at 2 or 3 occasions was associated with lower Mini-Mental State Examination scores and scores of memory and executive function in analyses adjusted for age, sex, and education [difference (95% CI) in mean ''T'' scores compared with normal-weight group: -1.51 (-2.77, -0.25), -1.27 (-2.46, -0.07), and -1.35 (-2.45, -0.24), respectively]. Participants who were underweight at > or =2 occasions from early adulthood to late midlife had lower executive function [difference (95% CI) in mean ''T'' score: -4.57 (-6.94, -2.20)]. A large increase in BMI from early to late midlife was associated with lower executive function.CONCLUSIONS: Long-term obesity and long-term underweight in adulthood are associated with lower cognitive scores in late midlife. Public health messages should promote a healthy weight at all ages. should promote a healthy weight at all ages.)
Pon 2011 Malar J + (BACKGROUND: ''Anopheles stephensi'' mitoch … BACKGROUND: ''Anopheles stephensi'' mitochondrial malic enzyme (ME) emerged as having a relevant role in the provision of pyruvate for the Krebs' cycle because inhibition of this enzyme results in the complete abrogation of oxygen uptake by mitochondria. Therefore, the identification of ME in mitochondria from immortalized A. stephensi (ASE) cells and the investigation of the stereoselectivity of malate analogues are relevant in understanding the physiological role of ME in cells of this important malaria parasite vector and its potential as a possible novel target for insecticide development.METHODS: To characterize the mitochondrial ME from immortalized ASE cells (Mos. 43; ASE), mass spectrometry analyses of trypsin fragments of ME, genomic sequence analysis and biochemical assays were performed to identify the enzyme and evaluate its activity in terms of cofactor dependency and inhibitor preference.RESULTS: The encoding gene sequence and primary sequences of several peptides from mitochondrial ME were found to be highly homologous to the mitochondrial ME from Anopheles gambiae (98%) and 59% homologous to the mitochondrial NADP+-dependent ME isoform from Homo sapiens. Measurements of ME activity in mosquito mitochondria isolated from ASE cells showed that (i) Vmax with NAD+ was 3-fold higher than that with NADP+, (ii) addition of Mg2+ or Mn2+ increased the Vmax by 9- to 21-fold, with Mn2+ 2.3-fold more effective than Mg2+, (iii) succinate and fumarate increased the activity by 2- and 5-fold, respectively, at sub-saturating concentrations of malate, (iv) among the analogs of L-malate tested as inhibitors of the NAD+-dependent ME catalyzed reaction, small (2- to 3-carbons) organic diacids carrying a 2-hydroxyl/keto group behaved as the most potent inhibitors of ME activity (e.g., oxaloacetate, tartronic acid and oxalate).CONCLUSIONS: The biochemical characterization of Anopheles stephensi ME is of critical relevance given its important role in bioenergetics, suggesting that it is a suitable target for insecticide development.itable target for insecticide development.)
Ejarque 2019 Int J Obes (Lond) + (BACKGROUND: A functional population of adi … BACKGROUND: A functional population of adipocyte precursors, termed adipose-derived stromal/stem cells (ASCs), is crucial for proper adipose tissue (AT) expansion, lipid handling, and prevention of lipotoxicity in response to chronic positive energy balance. We previously showed that obese human subjects contain a dysfunctional pool of ASCs. Elucidation of the mechanisms underlying abnormal ASC function might lead to therapeutic interventions for prevention of lipotoxicity by improving the adipogenic capacity of ASCs.METHODS: Using epigenome-wide association studies, we explored the impact of obesity on the methylation signature of human ASCs and their differentiated counterparts. Mitochondrial phenotyping of lean and obese ASCs was performed. TBX15 loss- and gain-of-function experiments were carried out and western blotting and electron microscopy studies of mitochondria were performed in white AT biopsies from lean and obese individuals.RESULTS: We found that DNA methylation in adipocyte precursors is significantly modified by the obese environment, and adipogenesis, inflammation, and immunosuppression were the most affected pathways. Also, we identified TBX15 as one of the most differentially hypomethylated genes in obese ASCs, and genetic experiments revealed that TBX15 is a regulator of mitochondrial mass in obese adipocytes. Accordingly, morphological analysis of AT from obese subjects showed an alteration of the mitochondrial network, with changes in mitochondrial shape and number.CONCLUSIONS: We identified a DNA methylation signature in adipocyte precursors associated with obesity, which has a significant impact on the metabolic phenotype of mature adipocytes. metabolic phenotype of mature adipocytes.)
Heymsfield 2007 Am J Clin Nutr + (BACKGROUND: Although Quetelet first report … BACKGROUND: Although Quetelet first reported in 1835 that adult weight scales to the square of stature, limited or no information is available on how anatomical body compartments, including adipose tissue (AT), scale to height.OBJECTIVE: We examined the critical underlying assumptions of adiposity-body mass index (BMI) relations and extended these analyses to major anatomical compartments: skeletal muscle (SM), bone, residual mass, weight (AT+SM+bone), AT-free mass, and organs (liver, brain).DESIGN: This was a cross-sectional analysis of 2 body-composition databases: one including magnetic resonance imaging and dual-energy X-ray absorptiometry (DXA) estimates of evaluated components in adults (total ''N''=411; organs=76) and the other a larger DXA database (''N''=1346) that included related estimates of fat, fat-free mass, and bone mineral mass.RESULTS: Weight, primary lean components (SM, residual mass, AT-free mass, and fat-free mass), and liver scaled to height with powers of approximately 2 (all ''P''<0.001); bone and bone mineral mass scaled to height with powers >2 (2.31-2.48), and the fraction of weight as bone mineral mass was significantly (''P''<0.001) correlated with height in women. AT scaled weakly to height with powers of approximately 2, and adiposity was independent of height. Brain mass scaled to height with a power of 0.83 (''P''=0.04) in men and nonsignificantly in women; the fraction of weight as brain was inversely related to height in women (''P''=0.002).CONCLUSIONS: These observations suggest that short and tall subjects with equivalent BMIs have similar but not identical body composition, provide new insights into earlier BMI-related observations and thus establish a foundation for height-normalized indexes, and create an analytic framework for future studies.nd create an analytic framework for future studies.)
Morse 2012 J Infect Dis + (BACKGROUND: Although human immunodeficienc … BACKGROUND: Although human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) affect mitochondrial DNA (mtDNA) content and function, comprehensive evaluations of their effects on mitochondria in muscle, adipose tissue, and blood cells are limited.METHODS: Mitochondrial DNA quantification, mitochondrial genome sequencing, and gene expression analysis were performed on muscle, adipose tissue, and peripheral blood mononuclear cell (PBMC) samples from untreated HIV-positive patients, HIV-positive patients receiving nucleoside reverse transcriptase inhibitor (NRTI)-based ART, and HIV-negative controls.RESULTS: The adipose tissue mtDNA/nuclear DNA (nDNA) ratio was increased in untreated HIV-infected patients (ratio, 353) and decreased in those receiving ART (ratio, 162) compared with controls (ratio, 255; P < .05 for both comparisons); the difference between the 2 HIV-infected groups was also significant (P = .002). In HIV-infected participants, mtDNA/nDNA in adipose tissue correlated with the level of activation (CD38+ /HLA-DR+) for CD4+ and CD8+ lymphocytes. No significant differences in mtDNA content were noted in muscle or PMBCs among groups. Exploratory DNA microarray analysis identified differential gene expression between patient groups, including a subset of adipose tissue genes.CONCLUSIONS: HIV infection and ART have opposing effects on mtDNA content in adipose tissue; immune activation may mediate the effects of HIV, whereas NRTIs likely mediate the effects of ART.reas NRTIs likely mediate the effects of ART.)
Gallagher 2000 Am J Clin Nutr + (BACKGROUND: Although international interes … BACKGROUND: Although international interest in classifying subject health status according to adiposity is increasing, no accepted published ranges of percentage body fat currently exist. Empirically identified limits, population percentiles, and z scores have all been suggested as means of setting percentage body fat guidelines, although each has major limitations.OBJECTIVE: The aim of this study was to examine a potential new approach for developing percentage body fat ranges. The approach taken was to link healthy body mass index (BMI; in kg/m(2)) guidelines established by the National Institutes of Health and the World Health Organization with predicted percentage body fat.DESIGN: Body fat was measured in subjects from 3 ethnic groups (white, African American, and Asian) who were screened and evaluated at 3 universities [Cambridge (United Kingdom), Columbia (United States), and Jikei (Japan)] with use of reference body-composition methods [4-compartment model (4C) at 2 laboratories and dual-energy X-ray absorptiometry (DXA) at all 3 laboratories]. Percentage body fat prediction equations were developed based on BMI and other independent variables.RESULTS: A convenient sample of 1626 adults with BMIs < or =35 was evaluated. Independent percentage body fat predictor variables in multiple regression models included 1/BMI, sex, age, and ethnic group (''R'': values from 0.74 to 0.92 and SEEs from 2.8 to 5.4 % fat). The prediction formulas were then used to prepare provisional healthy percentage body fat ranges based on published BMI limits for underweight (<18.5), overweight (> or =25), and obesity (> or =30).CONCLUSION: This proposed approach and initial findings provide the groundwork and stimulus for establishing international healthy body fat ranges.or establishing international healthy body fat ranges.)
Bredholt T 2009 Mol Cancer + (BACKGROUND: An organic extract of the recr … BACKGROUND: An organic extract of the recreational herb khat (''Catha edulis'' Forsk.) triggers cell death in various leukemia cell lines ''in vitro''. The chemotherapeutics camptothecin, a plant alkaloid topoisomerase I inhibitor, was tested side-by-side with khat in a panel of acute myeloid leukemia cell lines to elucidate mechanisms of toxicity.RESULTS: Khat had a profound effect on MOLM-13 cells inducing mitochondrial damage, chromatin margination and morphological features of autophagy. The effects of khat on mitochondrial ultrastructure in MOLM-13 correlated with strongly impaired routine respiration, an effect neither found in the khat-resistant MV-4-11 cells nor in camptothecin treated cells. Enforced expression of anti-apoptotic Bcl-2 protein provided protection against camptothecin-induced cell death and partly against khat toxicity. Khat-induced cell death in MOLM-13 cells included reduced levels of anti-apoptotic Mcl-1 protein, while both khat and camptothecin induced c-FLIPL cleavage and procaspase-8 activation.CONCLUSION: Khat activated a distinct cell death pathway in sensitive leukemic cells as compared to camptothecin, involving mitochondrial damage and morphological features of autophagy. This suggests that khat should be further explored in the search for novel experimental therapeutics.earch for novel experimental therapeutics.)
Heymsfield 2014 Am J Clin Nutr + (BACKGROUND: Body mass index (BMI) is formu … BACKGROUND: Body mass index (BMI) is formulated on the assumption that body weight (BW) scales to height with a power of 2 (BW∝height(2)), independent of sex and race-ethnicity. Powers differing from 2 are observed in studies of selected samples, thus raising the question if BMI is a generalizable metric that makes BW independent of height across populations.OBJECTIVES: The objectives were to test the hypothesis that adult BW scales to height with a power of 2 independent of sex and race-ethnicity and to advance an understanding of BMI as a measure of shape by extending allometric analyses to waist circumference (WC).DESIGN: We conducted cross-sectional subject evaluations, including body composition, from the NHANES and the Korean NHANES (KNHANES). Variations of the allometric model (Y = αX(β)) were used to establish height scaling powers (β ± SE) across non-Hispanic white and black, Mexican American, and Korean men and women.RESULTS: Exploratory analyses in population samples established age and adiposity as important independent determinants of height scaling powers (i.e., β). After age and adiposity in the next series of analyses were controlled for, BW scaling powers were nonsignificantly different between race/ethnic groups within each sex group; WC findings were similar in women, whereas small but significant between-race differences were observed in the men. Sex differences in β values were nonsignificant except for BW in non-Hispanic blacks and WC in Koreans (''P'' < 0.05). Nationally representative powers for BW were (NHANES/KNHANES) 2.12 ± 0.05/2.11 ± 0.06 for men and 2.02 ± 0.04/1.99 ± 0.06 for women and for WC were 0.66 ± 0.03/0.67 ± 0.05 for men and 0.61 ± 0.04/0.56 ± 0.05 for women.CONCLUSIONS: Adult BW scales to height with a power of ∼2 across the 8 sex and race/ethnic groups, an observation that makes BMI a generalizable height-independent measure of shape across most populations. WC also follows generalizable scaling rules, a finding that has implications for defining body shape in populations who differ in stature.y shape in populations who differ in stature.)
Romero-Corral 2008 Int J Obes (Lond) + (BACKGROUND: Body mass index (BMI) is the m … BACKGROUND: Body mass index (BMI) is the most widely used measure to diagnose obesity. However, the accuracy of BMI in detecting excess body adiposity in the adult general population is largely unknown.METHODS: A cross-sectional design of 13 601 subjects (age 20-79.9 years; 49 % men) from the Third National Health and Nutrition Examination Survey. Bioelectrical impedance analysis was used to estimate body fat percent (BF%). We assessed the diagnostic performance of BMI using the World Health Organization reference standard for obesity of BF%>25 % in men and>35 % in women. We tested the correlation between BMI and both BF% and lean mass by sex and age groups adjusted for race.RESULTS: BMI-defined obesity (> or =30 kg m(-2)) was present in 19.1 % of men and 24.7 % of women, while BF%-defined obesity was present in 43.9 % of men and 52.3 % of women. A BMI> or =30 had a high specificity (men=95 %, 95 % confidence interval (CI), 94-96 and women=99 %, 95 % CI, 98-100), but a poor sensitivity (men=36 %, 95 % CI, 35-37 and women=49 %, 95 % CI, 48-50) to detect BF%-defined obesity. The diagnostic performance of BMI diminished as age increased. In men, BMI had a better correlation with lean mass than with BF%, while in women BMI correlated better with BF% than with lean mass. However, in the intermediate range of BMI (25-29.9 kg m(-2)), BMI failed to discriminate between BF% and lean mass in both sexes.CONCLUSIONS: The accuracy of BMI in diagnosing obesity is limited, particularly for individuals in the intermediate BMI ranges, in men and in the elderly. A BMI cutoff of> or =30 kg m(-2) has good specificity but misses more than half of people with excess fat. These results may help to explain the unexpected better survival in overweight/mild obese patients.pected better survival in overweight/mild obese patients.)
Hood 2019 Nutr Diabetes + (BACKGROUND: Body mass index (BMI) represen … BACKGROUND: Body mass index (BMI) represents a normalization of weight to height and is used to classify adiposity. While the capacity of BMI as an adiposity index has been experimentally validated in Caucasians, but there has been little testing Asian populations.METHODS: To determine whether weight scales to height squared in Asian Indians across the general population and in Asian Indian tribes an allometric analysis on the power law model, ''W'' =''αHβ'', where ''W'' is weight (kg) and ''H'' is height (m) was performed on cross-sectional weight and height data from India (''N'' = 43,880) collected through the Anthropological Survey of India. The database contained males 18-84 years of age spanning 161 districts of 14 states and including 33 different tribes (''N'' = 5,549). Models were developed that were unadjusted and adjusted for tribe membership. The Korean National Health and Nutrition Examination Survey (KNHANES) was used to compare to height-weight data from the Anthropological Survey of India and to calculate BMI thresholds for obesity status using a receiver operating characteristic.RESULTS: The unadjusted power was ''β'' = 2.08 (s = 0.02). The power for the general population (non-tribal) was ''β'' = 2.11 (s = 0.02). Powers when adjusted for tribe ranged from 1.87 to 2.35 with 24 of the 33 tribes resulting in statistically significant (''p'' < 0.05) differences in powers from the general population. The coefficients of the adjusted terms ranged from -0.22 to 0.26 and therefore the scaling exponent does not deviate far from 2. Thresholds for BMI classification of overweight in the KNHANES database were BMI = 21 kg/m2 (AUC = 0.89) for males 18 kg/m2 (AUC = 0.97) for females. Obesity classification was calculated as BMI = 26 kg/m2 (AUC = 0.81) and 23 kg/m2 (AUC = 0.83) for females.CONCLUSIONS: Our study confirms that weight scales to height squared in Asian Indian males even after adjusting for tribe membership. We also demonstrate that optimal BMI thresholds are lower in a Korean population in comparison to currently used BMI thresholds. These results support the application of BMI in Asian populations with potentially lower thresholds.opulations with potentially lower thresholds.)
Sperrin 2016 J Public Health (Oxf) + (BACKGROUND: Body mass index (BMI) tends to … BACKGROUND: Body mass index (BMI) tends to be higher among shorter adults, especially women. The dependence of BMI-height correlation on age and calendar time may inform us about temporal determinants of BMI.METHODS: Series of cross-sectional surveys: Health Survey for England, 1992-2011. We study the Benn Index, which is the coefficient in a regression of log(weight) on log(height). This is adjusted for age, gender and calendar time, allowing for non-linear terms and interactions.RESULTS: By height quartile, mean BMI decreased with increasing height, more so in women than in men (P < 0.001). The decrease in mean BMI in the tallest compared with the shortest height quartile was 0.77 in men (95% CI 0.69, 0.86) and 1.98 in women (95% CI 1.89, 2.08). Regression analysis of log(weight) on log(height) revealed that the inverse association between BMI and height was more pronounced in older adults and stronger in women than in men, with little change over calendar time.CONCLUSIONS: Unlike early childhood, where taller children tend to have higher BMI, adults, especially women and older people, show an inverse BMI-height association. BMI is a heterogeneous measure of weight-for-height; height may be an important and complex determinant of BMI trajectory over the life course.© The Author 2015. Published by Oxford University Press on behalf of Faculty of Public Health. Press on behalf of Faculty of Public Health.)
Silbert 2016 J Alzheimers Dis + (BACKGROUND: Computer use is becoming a com … BACKGROUND: Computer use is becoming a common activity in the daily life of older individuals and declines over time in those with mild cognitive impairment (MCI). The relationship between daily computer use (DCU) and imaging markers of neurodegeneration is unknown.OBJECTIVE: The objective of this study was to examine the relationship between average DCU and volumetric markers of neurodegeneration on brain MRI.METHODS: Cognitively intact volunteers enrolled in the Intelligent Systems for Assessing Aging Change study underwent MRI. Total in-home computer use per day was calculated using mouse movement detection and averaged over a one-month period surrounding the MRI. Spearman's rank order correlation (univariate analysis) and linear regression models (multivariate analysis) examined hippocampal, gray matter (GM), white matter hyperintensity (WMH), and ventricular cerebral spinal fluid (vCSF) volumes in relation to DCU. A voxel-based morphometry analysis identified relationships between regional GM density and DCU.RESULTS: Twenty-seven cognitively intact participants used their computer for 51.3 minutes per day on average. Less DCU was associated with smaller hippocampal volumes (''r'' = 0.48, ''p'' = 0.01), but not total GM, WMH, or vCSF volumes. After adjusting for age, education, and gender, less DCU remained associated with smaller hippocampal volume (''p'' = 0.01). Voxel-wise analysis demonstrated that less daily computer use was associated with decreased GM density in the bilateral hippocampi and temporal lobes.CONCLUSIONS: Less daily computer use is associated with smaller brain volume in regions that are integral to memory function and known to be involved early with Alzheimer's pathology and conversion to dementia. Continuous monitoring of daily computer use may detect signs of preclinical neurodegeneration in older individuals at risk for dementia.in older individuals at risk for dementia.)
Pearson-Stuttard 2018 Lancet Diabetes Endocrinol + (BACKGROUND: Diabetes and high body-mass in … BACKGROUND: Diabetes and high body-mass index (BMI) are associated with increased risk of several cancers, and are increasing in prevalence in most countries. We estimated the cancer incidence attributable to diabetes and high BMI as individual risk factors and in combination, by country and sex.METHODS: We estimated population attributable fractions for 12 cancers by age and sex for 175 countries in 2012. We defined high BMI as a BMI greater than or equal to 25 kg/m2. We used comprehensive prevalence estimates of diabetes and BMI categories in 2002, assuming a 10-year lag between exposure to diabetes or high BMI and incidence of cancer, combined with relative risks from published estimates, to quantify contribution of diabetes and high BMI to site-specific cancers, individually and combined as independent risk factors and in a conservative scenario in which we assumed full overlap of risk of diabetes and high BMI. We then used GLOBOCAN cancer incidence data to estimate the number of cancer cases attributable to the two risk factors. We also estimated the number of cancer cases in 2012 that were attributable to increases in the prevalence of diabetes and high BMI from 1980 to 2002. All analyses were done at individual country level and grouped by region for reporting.FINDINGS: We estimated that 5·7 % of all incident cancers in 2012 were attributable to the combined effects of diabetes and high BMI as independent risk factors, corresponding to 804 100 new cases. 187 600 (24·5 %) of 766 000 cases of liver cancer and 121 700 (38·4 %) of 317 000 cases of endometrial cancer were attributable to these risk factors. In the conservative scenario, about 4·5 % (629 000 new cases) of all incident cancers assessed were attributable to diabetes and high BMI combined. Individually, high BMI (544 300 cases) was responsible for almost twice as many cancer cases as diabetes (293 300 cases). 25·8 % of diabetes-related cancers (equating to 75 600 new cases) and 31·9 % of high BMI-related cancers (174 040 new cases) were attributable to increases in the prevalence of these risk factors from 1980 to 2002.INTERPRETATION: A substantial number of cancer cases are attributable to diabetes and high BMI. As the prevalence of these cancer risk factors increases, clinical and public health efforts should focus on identifying optimal preventive and screening measures for whole populations and individual patients.FUNDING: NIHR and Wellcome Trust.Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd. All rights reserved.Corrected and republished from: Worldwide burden of cancer attributable to diabetes and high body-mass index: a comparative risk assessment [Lancet Diabetes Endocrinol 2018]sessment [Lancet Diabetes Endocrinol 2018])
Cohen 2008 Am J Clin Nutr + (BACKGROUND: During the past 40 y, there ha … BACKGROUND: During the past 40 y, there has been a trend toward more eating away from home, increased food availability, the opportunity to order extra-large portion sizes, and general weight gain.OBJECTIVE: Because shorter people need fewer calories than taller people to maintain their weight, our goal was to determine whether the body mass index (BMI)-height relation has changed over time.DESIGN: Data are from 3581 nonpregnant women and 3091 men examined in the 1959-1962 National Health Examination Survey and 4651 nonpregnant women and 4691 men examined in the 2001-2004 National Health and Nutrition Examination Survey. We tested whether the relation between BMI and height has changed for men and women, after adjustment for other demographic changes.RESULTS: In the past, on average, shorter American men and women had significantly higher BMIs than taller people. However, taller people have been increasing their BMI during the past 40 y at a faster rate than shorter people.CONCLUSIONS: This study documents that the obesity epidemic has changed the height-BMI relation. The data cannot identify causal pathways, and there are numerous explanations. A plausible hypothesis is that changes in the food environment may have eliminated constraints on weight gain for taller people that existed in a more calorie-constrained environment.in a more calorie-constrained environment.)
Rhein 2010 PloS One + (BACKGROUND: Energy deficiency and mitochon … BACKGROUND: Energy deficiency and mitochondrial failure have been recognized as a prominent, early event in Alzheimer's disease (AD). Recently, we demonstrated that chronic exposure to amyloid-beta (Abeta) in human neuroblastoma cells over-expressing human wild-type amyloid precursor protein (APP) resulted in (i) activity changes of Complexes III and IV of the oxidative phosphorylation system (OXPHOS) and in (ii) a drop of ATP levels which may finally instigate loss of synapses and neuronal cell death in AD. Therefore, the aim of the present study was to investigate whether standardized Ginkgo biloba extract LI 1370 (GBE) is able to rescue Abeta-induced defects in energy metabolism.METHODOLOGY/PRINCIPAL FINDINGS: We used a high-resolution respiratory protocol to evaluate OXPHOS respiratory capacity under physiological condition in control (stably transfected with the empty vector) and APP cells after treatment with GBE. In addition, oxygen consumption of isolated mitochondria, activities of mitochondrial respiratory enzymes, ATP and reactive oxygen species (ROS) levels as well as mitochondrial membrane mass and mitochondrial DNA content were determined. We observed a general antioxidant effect of GBE leading to an increase of the coupling state of mitochondria as well as energy homeostasis and a reduction of ROS levels in control cells and in APP cells. GBE effect on OXPHOS was even preserved in mitochondria after isolation from treated cells. Moreover, these functional data were paralleled by an up-regulation of mitochondrial DNA. Improvement of the OXPHOS efficiency was stronger in APP cells than in control cells. In APP cells, the GBE-induced amelioration of oxygen consumption most likely arose from the modulation and respective normalization of the Abeta-induced disturbance in the activity of mitochondrial Complexes III and IV restoring impaired ATP levels possibly through decreasing Abeta and oxidative stress level.CONCLUSIONS/SIGNIFICANCE: Although the underlying molecular mechanisms of the mode of action of GBE remain to be determined, our study clearly highlights the beneficial effect of GBE on the cellular OXPHOS performance and restoration of Abeta-induced mitochondrial dysfunction.f Abeta-induced mitochondrial dysfunction.)
Ekelund 2016 Lancet + (BACKGROUND: High amounts of sedentary beha … BACKGROUND: High amounts of sedentary behaviour have been associated with increased risks of several chronic conditions and mortality. However, it is unclear whether physical activity attenuates or even eliminates the detrimental effects of prolonged sitting. We examined the associations of sedentary behaviour and physical activity with all-cause mortality.METHODS: We did a systematic review, searching six databases (PubMed, PsycINFO, Embase, Web of Science, Sport Discus, and Scopus) from database inception until October, 2015, for prospective cohort studies that had individual level exposure and outcome data, provided data on both daily sitting or TV-viewing time and physical activity, and reported effect estimates for all-cause mortality, cardiovascular disease mortality, or breast, colon, and colorectal cancer mortality. We included data from 16 studies, of which 14 were identified through a systematic review and two were additional unpublished studies where pertinent data were available. All study data were analysed according to a harmonised protocol, which categorised reported daily sitting time and TV-viewing time into four standardised groups each, and physical activity into quartiles (in metabolic equivalent of task [MET]-hours per week). We then combined data across all studies to analyse the association of daily sitting time and physical activity with all-cause mortality, and estimated summary hazard ratios using Cox regression. We repeated these analyses using TV-viewing time instead of daily sitting time.FINDINGS: Of the 16 studies included in the meta-analysis, 13 studies provided data on sitting time and all-cause mortality. These studies included 1 005 791 individuals who were followed up for 2-18·1 years, during which 84 609 (8·4%) died. Compared with the referent group (ie, those sitting <4 h/day and in the most active quartile [>35·5 MET-h per week]), mortality rates during follow-up were 12-59% higher in the two lowest quartiles of physical activity (from HR=1·12, 95% CI 1·08-1·16, for the second lowest quartile of physical activity [<16 MET-h per week] and sitting <4 h/day; to HR=1·59, 1·52-1·66, for the lowest quartile of physical activity [<2·5 MET-h per week] and sitting >8 h/day). Daily sitting time was not associated with increased all-cause mortality in those in the most active quartile of physical activity. Compared with the referent (<4 h of sitting per day and highest quartile of physical activity [>35·5 MET-h per week]), there was no increased risk of mortality during follow-up in those who sat for more than 8 h/day but who also reported >35·5 MET-h per week of activity (HR=1·04; 95% CI 0·99-1·10). By contrast, those who sat the least (<4 h/day) and were in the lowest activity quartile (<2·5 MET-h per week) had a significantly increased risk of dying during follow-up (HR=1·27, 95% CI 1·22-1·31). Six studies had data on TV-viewing time (N=465 450; 43 740 deaths). Watching TV for 3 h or more per day was associated with increased mortality regardless of physical activity, except in the most active quartile, where mortality was significantly increased only in people who watched TV for 5 h/day or more (HR=1·16, 1·05-1·28).sed only in people who watched TV for 5 h/day or more (HR=1·16, 1·05-1·28).)
Bienholz 2011 Abstract IOC65 + (BACKGROUND: Hypoxia/reoxygenation (H/R) of … BACKGROUND: Hypoxia/reoxygenation (H/R) of proximal tubules leads to persistent ATP depletion due to decreased mitochondrial membrane potential (MMP) resulting from nonesterified fatty acid (NEFA)-mediated uncoupling that is paradoxically accompanied by respiratory inhibition rather than the stimulation expected for uncoupled states.METHODS: Since NEFA have been reported to directly inhibit electron transport in some settings we assessed respiratory function in isolated, permeabilized rabbit tubules after H/R as a function of NEFA availability.RESULTS: Compared to respiration supported by the complex II-dependent substrate, succinate, which was highly uncoupled after H/R but relatively well preserved (ADP-stimulated respiration (S3) of permeabilized tubules 71.0±8.5% of normoxic control (NC)), respiration supported by complex I-dependent substrates that normally predominate in cells was also uncoupled, but S3 was reduced to 26.9±3.3% of NC, P < 0.001 vs. succinate, N=5. With complex I substrates, acutely lowering NEFA after permeabilization improved coupling but only minimally increased S3. In contrast, lowering NEFA during 60 min. of reoxygenation prior to permeabilization increased S3 supported by complex I substrates, but it remained lower (55.7±7.5% of NC) than with succinate after the same treatment, 80.0±4.8%, p < 0.02. MMP at the end of H/R was much lower with complex I substrates (30.7±9.2% NC) than with succinate (67.4±4.5%), P < 0.004. Lowering NEFA during 60 min. of reoxygenation strongly improved recovery and decreased the MMP difference between complex I substrates (73.3±5.1% of NC) and succinate (83.4±6.6%).CONCLUSION: The studies indicate that selectively impaired utilization of complex I substrates to support respiration after H/R promotes NEFA-induced deenergization and is only minimally improved by acutely removing NEFA. In the presence of NEFA, the higher efficiency of complex I substrates to support electron transport does not mitigate the impact of the impaired respiration on MMP. However, lowering NEFA within cells for 60 min. allows strong recovery of MMP despite persistence of some respiratory impairment.despite persistence of some respiratory impairment.)
Bonthuis 2013 PLOS ONE + (BACKGROUND: In children with either delaye … BACKGROUND: In children with either delayed or accelerated growth, expressing the body mass index (BMI) to chronological age might lead to invalid body composition estimates. Reference to height-age has been suggested for such populations; however its validity has not been demonstrated.METHODS: Anthropometric data of healthy children were obtained from the German KiGGS survey. We selected three samples with different height distributions representing short stature (mean height SDS: -1.6), normal stature (height SDS: 0), and tall stature (height SDS: +1.6), and compared BMI-for-age and BMI-for-height-age between these samples across the paediatric age range. Differences between samples were tested using Kruskal-Wallis one-way analysis of variance and permutation tests.RESULTS: At a given age, BMI was distributed towards lower values in short, and towards higher values in tall subjects as compared to a population with average height distribution. Expressing BMI to height-age eliminated these differences in boys with a short stature from 4 years to 14 years of age, in tall boys from 4 to 16 years, in short girls aged 2-10 years or tall girls aged 2-17 years.CONCLUSION: From late infancy to adolescent age, BMI distribution co-varies with height distribution and referencing to height-age appears appropriate within this age period. However, caution is needed when data about pubertal status are absent.hen data about pubertal status are absent.)
Tompuri 2015 Clin Physiol Funct Imaging + (BACKGROUND: In the exercise testing measur … BACKGROUND: In the exercise testing measures of cardiorespiratory fitness need to be scaled by body size or composition to enable comparison between individuals. Traditionally used weight-proportional measures are potentially confounded by body adiposity that hampers their interpretation and applicability in the clinical assessment of cardiorespiratory fitness.OBJECTIVE: We aimed to find the most appropriate measure of body size or composition for scaling of measures of cardiorespiratory fitness among children.METHODS: We assessed body weight and height, maximal workload (''W''max) and maximal oxygen uptake (''V''O2max) using cycle ergometer exercise test with respiratory gas analysis and body lean mass (LM) and fat mass (FM) by dual-energy X-ray absorptiometry and by bioimpedance analysis among 38 children. The data were analysed using Pearson's coefficients for correlation and stepwise linear regression models.RESULTS: Lean mass (''r'' > 0.54) and height (''r'' > 0.51) had stronger positive correlations with absolute ''W''max and ''V''O2max than weight (''r'' > 0.30) in girls and boys. None of the measures of body size or composition correlated with LM-proportional ''W''max or ''V''O2max in girls or boys. Only LM correlated positively with height-proportional ''W''max (''r'' = 0.65) and ''V''O2max (''r'' = 0.71) in boys. FM correlated negatively with weight-proportional ''W''max (''r'' < -0.58) and ''V''O2max (''r'' < -0.64) in girls and boys. FM was even stronger determinant of weight-proportional ''W''max (''β'' = -0.68) and ''V''O2max (''β'' = -0.61) than exercise performance in multivariate linear regression models.CONCLUSIONS: While assessing cardiorespiratory fitness, LM is the most appropriate measure of body size or composition for scaling of ''W''max and ''V''O2max, because scaling by body weight introduces confounding by body adiposity.ss, LM is the most appropriate measure of body size or composition for scaling of ''W''max and ''V''O2max, because scaling by body weight introduces confounding by body adiposity.)
Kuper 2014 BMC Public Health + (BACKGROUND: Indians may be particularly vu … BACKGROUND: Indians may be particularly vulnerable to cardiometabolic disease, potentially due to higher body fat for a given BMI, or a tendency towards depositing abdominal adiposity. The aim of the study is to assess whether different measures of the distribution of adiposity (abdominal versus whole body) or amount of adiposity (DXA versus traditional anthropometric) are better at predicting prevalent cardiometabolic risk markers in an Indian population.METHODS: Participants were recruited from the Indian Migration Study (IMS) and the Andhra Pradesh Children and Parent Study (APCAPS). Participants attended a clinic in Hyderabad, India, January 2009-December 2010. Adiposity was measured by conventional anthropometry (including weight, height, waist) and DXA scanning (whole body and abdominal). Blood samples were taken and assessed for fasting plasma glucose, insulin, cholesterol, and triglycerides and blood pressure was measured. Lifestyle data were collected by questionnaire.RESULTS: We invited 4 617 participants to the clinic (1 995 IMS; 2 622 APCAPS) and examined 918 from IMS (46 %) and 1 451 from APCAPS (55 %). There were strong and consistent relationships between adiposity and cardiometabolic risk factors. Cardiometabolic risk factors did not appear to be more strongly associated with DXA measures as opposed to BMI, or skinfold measures of body fat. There was some evidence that WHR was more closely related to diabetes than total body adiposity, but this was not apparent for the other measures of abdominal adiposity (DXA measures, waist circumference) or other cardiometablic risk factors.CONCLUSIONS: No strong evidence supports that DXA measures or abdominal measures of adiposity are better at predicting the prevalence of cardiometabolic risk factors in comparison to BMI.tabolic risk factors in comparison to BMI.)
Nouette-Gaulain 2009 Anesthesiology + (BACKGROUND: Local anesthetics offer the be … BACKGROUND: Local anesthetics offer the benefits of extended analgesia with greater patient satisfaction and faster rehabilitation compared with intravenous morphine. These benefits, however, can be offset by adverse iatrogenic muscle pain caused by bupivacaine. Here, the authors describe the mechanisms of local anesthetic-induced myotoxicity and a partial protective effect of recombinant human erythropoietin (rhEPO).METHODS: The authors developed a rat analgesia model with femoral nerve catheter and a cell culture model of human skeletal muscle myoblasts to study local anesthetic effects. Rats were randomly assigned to four different groups: daily intraperitoneal injection with 5,000 U/kg rhEPO or saline coupled to a perineural catheter injection with 1 ml/kg bupivacaine, 0.25%, or saline. In psoas rat muscle, oxygen consumption rates were measured using a Clark-type electrode in saponin-skinned fibers. Mitochondrial adenosine triphosphate synthesis rates were determined by bioluminescence. Enzymatic activity of mitochondrial respiratory chain complexes was measured on tissue homogenates using spectrophotometric procedures, and mitochondrial morphology was analyzed by transmission electron microscopy. In addition, the interaction between bupivacaine and rhEPO was investigated on human skeletal muscle myoblasts by fluorescence microscopy using mitotracker green and using the lipophilic cation JC-1.RESULTS: Bupivacaine caused impairment of mitochondrial structure and bioenergetics in rats. Human myoblasts treated with bupivacaine showed a dose-dependent decrease in mitochondrial membrane potential associated with unusual morphologies. Impairment of mitochondrial bioenergetics was prevented partially by the use of rhEPO coadministered with bupivacaine.CONCLUSIONS: The authors demonstrated a dose- and time-dependent protective effect of rhEPO against bupivacaine-induced myotoxicity in regional analgesia.induced myotoxicity in regional analgesia.)
Xu 1999 Structure + (BACKGROUND: Malic enzymes catalyze the oxi … BACKGROUND: Malic enzymes catalyze the oxidative decarboxylation of malate to pyruvate and CO2 with the concomitant reduction of NAD(P)+ to NAD(P)H. They are widely distributed in nature and have important biological functions. Human mitochondrial NAD(P)+-dependent malic enzyme (mNAD-ME) may have a crucial role in the metabolism of glutamine for energy production in rapidly dividing cells and tumors. Moreover, this isoform is unique among malic enzymes in that it is a cooperative enzyme, and its activity is controlled allosterically.RESULTS: The crystal structure of human mNAD-ME has been determined at 2.5 A resolution by the selenomethionyl multiwavelength anomalous diffraction method and refined to 2.1 A resolution. The structure of the monomer can be divided into four domains; the active site of the enzyme is located in a deep cleft at the interface between three of the domains. Three acidic residues (Glu255, Asp256 and Asp279) were identified as ligands for the divalent cation that is required for catalysis by malic enzymes.CONCLUSIONS: The structure reveals that malic enzymes belong to a new class of oxidative decarboxylases. The tetramer of the enzyme appears to be a dimer of dimers. The active site of each monomer is located far from the tetramer interface. The structure also shows the binding of a second NAD+ molecule in a pocket 35 A away from the active site. The natural ligand for this second binding site may be ATP, an allosteric inhibitor of the enzyme.TP, an allosteric inhibitor of the enzyme.)
Lucchinetti 2012 Anesthesiology + (BACKGROUND: Mesenchymal stem cells (MSC) a … BACKGROUND: Mesenchymal stem cells (MSC) are self-renewing clonal progenitor cells of nonhematopoietic tissues that exhibit a marked tropism to wounds and tumors. The authors' studies aimed at exploring how local anesthetics would affect MSC biology.METHODS: Proliferation, colony formation, ''in vitro'' wound healing, and bone differentiation assays of culture-expanded bone-marrow-derived murine MSC were performed in the presence of increasing concentrations of lidocaine, ropivacaine, and bupivacaine. Cytotoxicity was monitored by measuring lactate dehydrogenase activity and phosphatidylserine exposure/propidium iodide staining (early apoptotic cells/necrotic cells). Measurements of mitochondrial function in intact and permeabilized cells, transcriptional changes, and changes in nuclear factor κ-light-chain-enhancer of activated B cells signaling in MSC treated with ropivacaine were used to further characterize the biologic effects of local anesthetics on MSC.RESULTS: All local anesthetics reduced MSC proliferation at 100 μM, consistent with cell cycle delay or arrest at the G0/1-S phase transition. They increased lactate dehydrogenase release and the number of annexin V-positive MSC but not necrotic MSC. Colony formation was decreased, differentiation into osteoblasts impaired, and ''in vitro'' wound healing delayed. Mitochondrial respiration and adenosine 5'-triphosphate concentrations were reduced. Microarray analysis revealed significant expression changes in lysosomal genes and genes controlling sterol metabolism, indicating an impaired phospholipid metabolism in the lysosome. Multiple transcriptional programs related to cell differentiation, tumorigenesis, and metastasis were negatively affected by ropivacaine.CONCLUSIONS: The authors' studies demonstrate that local anesthetics significantly affect important aspects of MSC biology. These experiments provide novel rationales for the perioperative use of local anesthetics in patients with cancer but also highlight the potentially detrimental effects of local anesthetics on wound healing.cts of local anesthetics on wound healing.)
Gispert 2009 PLoS One + (BACKGROUND: Parkinson's disease (PD) is an … BACKGROUND: Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.METHODOLOGY/PRINCIPAL FINDINGS: Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of α-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in ''Drosophila melanogaster'' and in spite of reduced expression of fission factor ''Mtp18'', we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons.CONCLUSION: Thus, aging ''Pink1(-/-)'' mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.to PD, in absence of overt neuronal death.)
Raji 2016 J Alzheimers Dis + (BACKGROUND: Physical activity (PA) can be … BACKGROUND: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer's disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual.OBJECTIVE: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons.METHODS: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent.RESULTS: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis.CONCLUSION: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status.e elderly, regardless of cognitive status.)
Meyer 2010 Eur J Cardiovasc Prev Rehabil + (BACKGROUND: Population strategies to incre … BACKGROUND: Population strategies to increase physical activity are an essential part of cardiovascular disease prevention. However, little data exist on lifestyle interventions that are easy to integrate into everyday life such as using stairs instead of elevators at the workplace.DESIGN: Pre and postintervention study.METHODS: A 12-week promotional campaign for stair use consisting in posters and floor stickers at the point of choice between stairs and elevators at each hospital floor was organized in a university hospital building. In 77 selected employees with an inactive lifestyle, physical activity, aerobic fitness, anthropometrics, blood pressure, lipids, insulin sensitivity, and C-reactive protein were assessed at baseline, 12 weeks, and 6 months.RESULTS: During the intervention median daily number of ascended and descended one-story staircase units was 20.6/day (14.2-28.1) compared with 4.5/day (1.8-7.2) at baseline (''P''<0.001). At 12 weeks, estimated maximal aerobic capacity had increased by 9.2±15.1% (''P''<0.001) corresponding with approximately 1 MET. There were significant declines in waist circumference (-1.7±2.9%), weight (-0.7±2.6%), fat mass (-1.5±8.4%), diastolic blood pressure (-1.8±8.9%), and low-density lipoprotein cholesterol (-3.0±13.5%). At 6 months, the median daily number of ascended and descended one-story staircase units had decreased to 7.2 (3.5-14.0). Benefits on estimated maximal aerobic capacity (+5.9±12.2%, ''P''=0.001) and fat mass (-1.4±8.4%, ''P''=0.038) persisted.CONCLUSION: Encouraging stair use at work is effective for improving fitness, body composition, blood pressure, and lipid profile in asymptomatic individuals with an inactive lifestyle and thus may be a simple way to significantly reduce cardiovascular disease risk at the population level.iovascular disease risk at the population level.)
Grocott 2009 N Engl J Med + (BACKGROUND: The level of environmental hyp … BACKGROUND: The level of environmental hypobaric hypoxia that affects climbers at the summit of Mount Everest (8848 m [29,029 ft]) is close to the limit of tolerance by humans. We performed direct field measurements of arterial blood gases in climbers breathing ambient air on Mount Everest.METHODS: We obtained samples of arterial blood from 10 climbers during their ascent to and descent from the summit of Mount Everest. The partial pressures of arterial oxygen (PaO(2)) and carbon dioxide (PaCO(2)), pH, and hemoglobin and lactate concentrations were measured. The arterial oxygen saturation (SaO(2)), bicarbonate concentration, base excess, and alveolar-arterial oxygen difference were calculated.RESULTS: PaO(2) fell with increasing altitude, whereas SaO(2) was relatively stable. The hemoglobin concentration increased such that the oxygen content of arterial blood was maintained at or above sea-level values until the climbers reached an elevation of 7100 m (23,294 ft). In four samples taken at 8400 m (27,559 ft)--at which altitude the barometric pressure was 272 mm Hg (36.3 kPa)--the mean PaO(2) in subjects breathing ambient air was 24.6 mm Hg (3.28 kPa), with a range of 19.1 to 29.5 mm Hg (2.55 to 3.93 kPa). The mean PaCO(2) was 13.3 mm Hg (1.77 kPa), with a range of 10.3 to 15.7 mm Hg (1.37 to 2.09 kPa). At 8400 m, the mean arterial oxygen content was 26% lower than it was at 7100 m (145.8 ml per liter as compared with 197.1 ml per liter). The mean calculated alveolar-arterial oxygen difference was 5.4 mm Hg (0.72 kPa).CONCLUSIONS: The elevated alveolar-arterial oxygen difference that is seen in subjects who are in conditions of extreme hypoxia may represent a degree of subclinical high-altitude pulmonary edema or a functional limitation in pulmonary diffusion.ctional limitation in pulmonary diffusion.)
Ding 2016 Lancet + (BACKGROUND: The pandemic of physical inact … BACKGROUND: The pandemic of physical inactivity is associated with a range of chronic diseases and early deaths. Despite the well documented disease burden, the economic burden of physical inactivity remains unquantified at the global level. A better understanding of the economic burden could help to inform resource prioritisation and motivate efforts to increase levels of physical activity worldwide.METHODS: Direct health-care costs, productivity losses, and disability-adjusted life-years (DALYs) attributable to physical inactivity were estimated with standardised methods and the best data available for 142 countries, representing 93·2% of the world's population. Direct health-care costs and DALYs were estimated for coronary heart disease, stroke, type 2 diabetes, breast cancer, and colon cancer attributable to physical inactivity. Productivity losses were estimated with a friction cost approach for physical inactivity related mortality. Analyses were based on national physical inactivity prevalence from available countries, and adjusted population attributable fractions (PAFs) associated with physical inactivity for each disease outcome and all-cause mortality.FINDINGS: Conservatively estimated, physical inactivity cost health-care systems international $ (INT$) 53·8 billion worldwide in 2013, of which $31·2 billion was paid by the public sector, $12·9 billion by the private sector, and $9·7 billion by households. In addition, physical inactivity related deaths contribute to $13·7 billion in productivity losses, and physical inactivity was responsible for 13·4 million DALYs worldwide. High-income countries bear a larger proportion of economic burden (80·8% of health-care costs and 60·4% of indirect costs), whereas low-income and middle-income countries have a larger proportion of the disease burden (75·0% of DALYs). Sensitivity analyses based on less conservative assumptions led to much higher estimates.INTERPRETATION: In addition to morbidity and premature mortality, physical inactivity is responsible for a substantial economic burden. This paper provides further justification to prioritise promotion of regular physical activity worldwide as part of a comprehensive strategy to reduce non-communicable diseases.ategy to reduce non-communicable diseases.)
Sarti 2011 Biochim Biophys Acta + (BACKGROUND: The reactions between Complex … BACKGROUND: The reactions between Complex IV (cytochrome c oxidase, CcOX) and nitric oxide (NO) were described in the early 60's. The perception, however, that NO could be responsible for physiological or pathological effects, including those on mitochondria, lags behind the 80's, when the identity of the endothelial derived relaxing factor (EDRF) and NO synthesis by the NO synthases were discovered. NO controls mitochondrial respiration, and cytotoxic as well as cytoprotective effects have been described. The depression of OXPHOS ATP synthesis has been observed, attributed to the inhibition of mitochondrial Complex I and IV particularly, found responsible of major effects.SCOPE OF REVIEW: The review is focused on CcOX and NO with some hints about pathophysiological implications. The reactions of interest are reviewed, with special attention to the molecular mechanisms underlying the effects of NO observed on cytochrome c oxidase, particularly during turnover with oxygen and reductants. MAJOR CONCLUSIONS ANDGENERAL SIGNIFICANCE: The NO inhibition of CcOX is rapid and reversible and may occur in competition with oxygen. Inhibition takes place following two pathways leading to formation of either a relatively stable nitrosyl-derivative (CcOX-NO) of the enzyme reduced, or a more labile nitrite-derivative (CcOX-NO(2)(-)) of the enzyme oxidized, and during turnover. The pathway that prevails depends on the turnover conditions and concentration of NO and physiological substrates, cytochrome c and O(2). All evidence suggests that these parameters are crucial in determining the CcOX vs NO reaction pathway prevailing in vivo, with interesting physiological and pathological consequences for cells. This article is part of a Special Issue entitled: Respiratory Oxidases.cial Issue entitled: Respiratory Oxidases.)
Hereng 2011 Hum Reprod + (BACKGROUND: There has been an ongoing deba … BACKGROUND: There has been an ongoing debate in the reproductive field about whether mammalian spermatozoa rely on glycolysis, oxidative phosphorylation or both for their energy production. Recent studies have proposed that human spermatozoa depend mainly on glucose for motility and fertilization but the mechanism behind an efficient glycolysis in human spermatozoa is not well understood. Here, we demonstrate how human spermatozoa utilize exogenous pyruvate to enhance glycolytic ATP production, motility, hyperactivation and capacitation, events that are crucial for male fertility.METHODS: Purified human spermatozoa from healthy donors were incubated under capacitating conditions (including albumin, bicarbonate and glucose) and tested for changes in ATP levels, motility, hyperactivation and tyrosine phosphorylation after treatment with pyruvate. The experiments were repeated in the presence of sodium cyanide in order to assess the contribution from mitochondrial respiration. The metabolism of (13)C labeled glucose and pyruvate was traced by a combination of liquid chromatography and mass spectrometry.RESULTS: The treatment of human spermatozoa with exogenous pyruvate increased intracellular ATP levels, progressive motility and hyperactivation by 56, 21 and 130%, respectively. In addition, added pyruvate induced a significant increase in tyrosine phosphorylation levels. Blocking of the electron transport chain did not markedly affect the results, indicating that the mechanism is independent of oxidative phosphorylation. However, the observed effects could be counteracted by oxamate, an inhibitor of lactate dehydrogenase (LDH). Metabolic tracing experiments revealed that the observed rise in ATP concentration resulted from an enhanced glycolytic flux, which was increased by more than 50% in the presence of exogenous pyruvate. Moreover, all consumed (13)C labeled pyruvate added was converted to lactate rather than oxidized in the tricarboxylic acid cycle.CONCLUSIONS: Human spermatozoa seem to rely mainly, if not entirely, on glycolysis as the source of ATP fueling the energy-demanding processes of motility and capacitation. The efficient glycolysis is dependent on exogenous pyruvate, which indirectly feeds the accelerated glycolysis with NAD(+) through the LDH-mediated conversion of pyruvate to lactate. Pyruvate is present in the human female reproductive tract at concentrations in accordance with our results. As seen in other mammals, the motility and fertility of human spermatozoa seem to be dictated by the available energy substrates present in the conspecific female.strates present in the conspecific female.)
Hoeks 2011 PLoS One + (BACKGROUND: Type 2 diabetes mellitus and m … BACKGROUND: Type 2 diabetes mellitus and muscle insulin resistance have been associated with reduced capacity of skeletal muscle mitochondria, possibly as a result of increased intake of dietary fat. Here, we examined the hypothesis that a prolonged high-fat diet consumption (HFD) increases the saturation of muscle mitochondrial membrane phospholipids causing impaired mitochondrial oxidative capacity and possibly insulin resistance.METHODOLOGY: C57BL/6J mice were fed an 8-week or 20-week low fat diet (10 kcal%; LFD) or HFD (45 kcal%). Skeletal muscle mitochondria were isolated and fatty acid (FA) composition of skeletal muscle mitochondrial phospholipids was analyzed by thin-layer chromatography followed by GC. High-resolution respirometry was used to assess oxidation of pyruvate and fatty acids by mitochondria. Insulin sensitivity was estimated by HOMA-IR.PRINCIPAL FINDINGS: At 8 weeks, mono-unsaturated FA (16∶1n7, 18∶1n7 and 18∶1n9) were decreased (-4.0%, p<0.001), whereas saturated FA (16∶0) were increased (+3.2%, p<0.001) in phospholipids of HFD vs. LFD mitochondria. Interestingly, 20 weeks of HFD descreased mono-unsaturated FA while n-6 poly-unsaturated FA (18∶2n6, 20∶4n6, 22∶5n6) showed a pronounced increase (+4.0%, p<0.001). Despite increased saturation of muscle mitochondrial phospholipids after the 8-week HFD, mitochondrial oxidation of both pyruvate and fatty acids were similar between LFD and HFD mice. After 20 weeks of HFD, the increase in n-6 poly-unsaturated FA was accompanied by enhanced maximal capacity of the electron transport chain (+49%, p = 0.002) and a tendency for increased ADP-stimulated respiration, but only when fuelled by a lipid-derived substrate. Insulin sensitivity in HFD mice was reduced at both 8 and 20 weeks.CONCLUSIONS/INTERPRETATION: Our findings do not support the concept that prolonged HF feeding leads to increased saturation of skeletal muscle mitochondrial phospholipids resulting in a decrease in mitochondrial fat oxidative capacity and (muscle) insulin resistance.oxidative capacity and (muscle) insulin resistance.)
NCD-RisC 2017 Lancet + (BACKGROUND: Underweight, overweight, and o … BACKGROUND: Underweight, overweight, and obesity in childhood and adolescence are associated with adverse health consequences throughout the life-course. Our aim was to estimate worldwide trends in mean body-mass index (BMI) and a comprehensive set of BMI categories that cover underweight to obesity in children and adolescents, and to compare trends with those of adults.METHODS: We pooled 2416 population-based studies with measurements of height and weight on 128·9 million participants aged 5 years and older, including 31·5 million aged 5-19 years. We used a Bayesian hierarchical model to estimate trends from 1975 to 2016 in 200 countries for mean BMI and for prevalence of BMI in the following categories for children and adolescents aged 5-19 years: more than 2 SD below the median of the WHO growth reference for children and adolescents (referred to as moderate and severe underweight hereafter), 2 SD to more than 1 SD below the median (mild underweight), 1 SD below the median to 1 SD above the median (healthy weight), more than 1 SD to 2 SD above the median (overweight but not obese), and more than 2 SD above the median (obesity).FINDINGS: Regional change in age-standardised mean BMI in girls from 1975 to 2016 ranged from virtually no change (-0·01 kg/m2 per decade; 95% credible interval -0·42 to 0·39, posterior probability [PP] of the observed decrease being a true decrease=0·5098) in eastern Europe to an increase of 1·00 kg/m2 per decade (0·69-1·35, PP>0·9999) in central Latin America and an increase of 0·95 kg/m2 per decade (0·64-1·25, PP>0·9999) in Polynesia and Micronesia. The range for boys was from a non-significant increase of 0·09 kg/m2 per decade (-0·33 to 0·49, PP=0·6926) in eastern Europe to an increase of 0·77 kg/m2 per decade (0·50-1·06, PP>0·9999) in Polynesia and Micronesia. Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls. By contrast, the rise in BMI has accelerated in east and south Asia for both sexes, and southeast Asia for boys. Global age-standardised prevalence of obesity increased from 0·7% (0·4-1·2) in 1975 to 5·6% (4·8-6·5) in 2016 in girls, and from 0·9% (0·5-1·3) in 1975 to 7·8% (6·7-9·1) in 2016 in boys; the prevalence of moderate and severe underweight decreased from 9·2% (6·0-12·9) in 1975 to 8·4% (6·8-10·1) in 2016 in girls and from 14·8% (10·4-19·5) in 1975 to 12·4% (10·3-14·5) in 2016 in boys. Prevalence of moderate and severe underweight was highest in India, at 22·7% (16·7-29·6) among girls and 30·7% (23·5-38·0) among boys. Prevalence of obesity was more than 30% in girls in Nauru, the Cook Islands, and Palau; and boys in the Cook Islands, Nauru, Palau, Niue, and American Samoa in 2016. Prevalence of obesity was about 20% or more in several countries in Polynesia and Micronesia, the Middle East and north Africa, the Caribbean, and the USA. In 2016, 75 (44-117) million girls and 117 (70-178) million boys worldwide were moderately or severely underweight. In the same year, 50 (24-89) million girls and 74 (39-125) million boys worldwide were obese.INTERPRETATION: The rising trends in children's and adolescents' BMI have plateaued in many high-income countries, albeit at high levels, but have accelerated in parts of Asia, with trends no longer correlated with those of adults.h trends no longer correlated with those of adults.)
Paech 2017 Arch Toxicol + (BAL30072 is a new monocyclic β-lactam anti … BAL30072 is a new monocyclic β-lactam antibiotic under development which provides a therapeutic option for the treatment of severe infections caused by multi-drug-resistant Gram-negative bacteria. Despite the absence of liver toxicity in preclinical studies in rats and marmosets and in single dose clinical studies in humans, increased transaminase activities were observed in healthy subjects in multiple-dose clinical studies. We, therefore, initiated a comprehensive program to find out the mechanisms leading to hepatocellular injury using HepG2 cells (human hepatocellular carcinoma cell line), HepaRG cells (inducible hepatocytes derived from a human hepatic progenitor cell line), and human liver microtissue preparations. Our investigations demonstrated a concentration- and time-dependent reduction of the ATP content of BAL30072-treated HepG2 cells and liver microtissues. BAL30072 impaired oxygen consumption by HepG2 cells at clinically relevant concentrations, inhibited complexes II and III of the mitochondrial electron transport chain, increased the production of reactive oxygen species (ROS), and reduced the mitochondrial membrane potential. Furthermore, BAL 30072 impaired mitochondrial fatty acid metabolism, inhibited glycolysis, and was associated with hepatocyte apoptosis. Co-administration of N-acetyl-L-cysteine partially protected hepatocytes from BAL30072-mediated toxicity, underscoring the role of oxidative damage in the observed hepatocellular toxicity. In conclusion, BAL30072 is toxic for liver mitochondria and inhibits glycolysis at clinically relevant concentrations. Impaired hepatic mitochondrial function and inhibition of glycolysis can explain liver injury observed in human subjects receiving long-term treatment with this compound.ng long-term treatment with this compound.)

10th World Gene Convention 2019 Qingdao CN + (BIT’s 10th World Gene Convention-2019 (WGC-2019), Qingdao, China, 2019)

Gururaja Rao 2019 Cells + (BKCa channels, orig … BKCa channels, originally discovered in ''Drosophila melanogaster'' as slowpoke (slo), are recognized for their roles in cellular and organ physiology. Pharmacological approaches implicated BKCa channels in cellular and organ protection possibly for their ability to modulate mitochondrial function. However, the direct role of BKCa channels in regulating mitochondrial structure and function is not deciphered. Here, we demonstrate that BKCa channels are present in fly mitochondria, and slo mutants show structural and functional defects in mitochondria. slo mutants display an increase in reactive oxygen species and the modulation of ROS affected their survival. We also found that the absence of BKCa channels reduced the lifespan of ''Drosophila'', and overexpression of human BKCa channels in flies extends life span in males. Our study establishes the presence of BKCa channels in mitochondria of ''Drosophila'' and ascertains its novel physiological role in regulating mitochondrial structural and functional integrity, and lifespan.a'' and ascertains its novel physiological role in regulating mitochondrial structural and functional integrity, and lifespan.)
Crislip 2022 Biomolecules + (BMAL1 is a core mammalian circadian clock … BMAL1 is a core mammalian circadian clock transcription factor responsible for the regulation of the expression of thousands of genes. Previously, male skeletal-muscle-specific BMAL1-inducible-knockout (iMS-BMAL1 KO) mice have been described as a model that exhibits an aging-like phenotype with an altered gait, reduced mobility, muscle weakness, and impaired glucose uptake. Given this aging phenotype and that chronic kidney disease is a disease of aging, the goal of this study was to determine if iMS-BMAL1 KO mice exhibit a renal phenotype. Male iMS-BMAL1 KO and control mice were challenged with a low potassium diet for five days. Both genotypes responded appropriately by conserving urinary potassium. The iMS-BMAL1 KO mice excreted less potassium during the rest phase during the normal diet but there was no genotype difference during the active phase. Next, iMS-BMAL1 KO and control mice were used to compare markers of kidney injury and assess renal function before and after a phase advance protocol. Following phase advance, no differences were detected in renal mitochondrial function in iMS-BMAL1 KO mice compared to control mice. Additionally, the glomerular filtration rate and renal morphology were similar between groups in response to phase advance. Disruption of the clock in skeletal muscle tissue activates inflammatory pathways within the kidney of male mice, and there is evidence of this affecting other organs, such as the lungs. However, there were no signs of renal injury or altered function following clock disruption of skeletal muscle under the conditions tested.eletal muscle under the conditions tested.)
BMES-SIG & MIG Conclave 2023 Virtual + (BMES-SIG & MIG Conclave, Virtual, 2023)
BMT 2022 Innsbruck AT + (BMT 2022, Innsbruck, 2022)
Osiki 2016 FASEB J + (Background Beta-oxidation is often measure … BackgroundBeta-oxidation is often measured using respirometry with octanoylcarnitine + malate as substrates in cells. Malate is necessary to ensure continuous oxidation of octanoylcarnitine. However, since malate is metabolized in the TCA cycle, it is not clear if its inclusion as a co-substrate allows for a valid assessment of beta-oxidation when TCA cycle function is compromised.AimTo investigate the validity of beta-oxidation assessment using octanoylcarnitine + malate as a substrate combination in skeletal muscle when mitochondrial (mt) aconitase is inhibited.MethodsSoleus muscle fibres (1.5–2mg) from healthy male Wistar rats were permeabilized with saponin and incubated for 45 minutes with 1mM oxalomalic acid (aconitase inhibitor) or 1mM 2-mercaptoacetate, an inhibitor of MCAD – the rate-limiting enzyme of octanoylcarnitine oxidation. Respiration at Leak, Oxphos and ET-pathway states were measured using an Oroboros oxygraph. Citrate and 2-oxoglutarate in the respiratory media were measured using CG-MS. Activities of aconitase and MCAD were determined spectrophotometrically.ResultsOxalomalic acid (1mM) and 1mM of 2-mercaptoacetate caused 24% and 58% inhibition of acnonitase and MCAD, respectively. Oxygen flux at Oxphos (0.5 ± 0.3 pmol.S−1.mg−1) and ET-pathway (0.6 ± 0.2 pmol.S−1.mg−1) decreased in 2-mercaptoacetate-treated samples by 62.5% and 60%, respectively, but were unchanged with oxalomalic acid treatment. Respiration at leak state was similar for all treatments. Citrate level in the medium increased by 2-fold at Oxphos state after 30 minutes.ConclusionOctanoylcarnitine + malate allows for a valid assessment of beta-oxidation capacity using respirometry under conditions where mt-aconitase has been inhibited.Support or Funding InformationSupport: 1. The research unit for Exercise Science & Sports Medicine at the University of Cape Town 2. The National Research Foundation (NRF), South Africa, for funding the research.FootnotesThis abstract is from the Experimental Biology 2016 Meeting. There is no full text article associated with this abstract published in The FASEB Journal. this abstract published in The FASEB Journal.)
Nesci 2016 Biochim Biophys Acta + (Background The mitochondrial F1FO-ATP synt … BackgroundThe mitochondrial F1FO-ATP synthase has not only the known life function in building most cellular ATP, but also, as recently hinted, an amazing involvement in cell death. Accordingly, the two-faced enzyme complex, which catalyzes both ATP synthesis and ATP hydrolysis, has been involved in the mitochondrial permeability transition, the master player in apoptosis and necrosis. Nitrite, a cellular nitric oxide reservoir, has a recognized role in cardiovascular protection, through still unclear mechanisms.MethodsIn swine heart mitochondria the effect of nitrite on the F1FO-ATPase activity activated by Ca2+, henceforth defined as Ca-ATPase(s), or by the natural cofactor Mg2+, was investigated by evaluating ATP hydrolysis under different assay conditions.ResultsCa2+ is far less efficient than the natural cofactor Mg2+ in the ATPase activation. However, when activated by Ca2+ the ATPase activity is especially responsive to nitrite, which acts as uncompetitive inhibitor and up to 2 mM inhibits the Ca2+-activated-ATPase(s), probably by promoting dytirosine formation on the enzyme proteins, leaving the Mg-ATPase(s) unaffected. Most likely these ATPases refer to the same F1FO complex, even if coexistent ATPases may overlap.ConclusionsThe preferential inhibition by nitrite of the Ca-ATPase(s), due to post-translational tyrosine modifications, may prevent the calcium-dependent functionality of the mitochondrial F1FO complex and related events.General significanceIn mitochondria the preferential inhibition of the Ca-ATPase activity/ies by nitrite concentrations which do not affect the coexistent Mg-ATPase(s) may quench the negative events linked to the calcium-dependent functioning mode of the F1FO complex under pathological conditions.egative events linked to the calcium-dependent functioning mode of the F1FO complex under pathological conditions.)
Rector 2010 J Hepatol + (Background & aims: In this study, we s … Background & aims: In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model.Methods: OLETF rats and their non-hyperphagic control Long-Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n=6-8 per group).Results: At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p<0.01) hepatic mitochondrial dysfunction as measured by reduced hepatic carnitine palmitoyl-CoA transferase-1 activity, fatty acid oxidation, and cytochrome c protein content compared with LETO rats. Hepatic TG levels were significantly elevated by 8 weeks of age, and insulin resistance developed by 13 weeks in the OLETF rats. NAFLD progressively worsened to include hepatocyte ballooning, perivenular fibrosis, 2.5-fold increase in serum ALT, hepatic mitochondrial ultrastructural abnormalities, and increased hepatic oxidative stress in the OLETF animals at later ages. Measures of hepatic mitochondrial content and function including beta-hydroxyacyl-CoA dehydrogenase activity, citrate synthase activity, and immunofluorescence staining for mitochondrial carbamoyl phosphate synthetase-1, progressively worsened and were significantly reduced at 40 weeks in OLETF rats compared to LETO animals.Conclusions: Our study documents that hepatic mitochondrial dysfunction precedes the development of NAFLD and insulin resistance in the OLETF rats. This evidence suggests that progressive mitochondrial dysfunction contributes to the natural history of obesity-associated NAFLD. the natural history of obesity-associated NAFLD.)
Noz 2019 J Am Heart Assoc + (Background Low-grade inflammation, largely … Background Low-grade inflammation, largely mediated by monocyte-derived macrophages, contributes to atherosclerosis. Sedentary behavior is associated with atherosclerosis and cardiovascular diseases (CVD). We examined whether reducing sedentary behavior and improving walking time improves monocyte inflammatory phenotype in subjects with increased cardiovascular risk. Methods and Results Across 2 waves, 16 individuals with increased cardiovascular risk performed a 16-week intervention study (age 64±6 years, body mass index 29.9±4.3 kg/m2), using a device with vibration feedback to promote physical activity. Before and after intervention, we objectively examined physical activity (ActivPAL), cytokine production capacity after ''ex vivo'' stimulation in peripheral blood mononuclear cells, metabolism of peripheral blood mononuclear cells, circulating cytokine concentrations, and monocyte immunophenotype. Overall, no significant increase in walking time was found (1.9±0.7 to 2.2±1.2 h/day, P=0.07). However, strong, inverse correlations were observed between the change in walking time and the change in production of interleukin (IL)-1β, IL-6, IL-8, and IL-10 after lipopolysaccharide stimulation (rs=-0.655, -0.844, -0.672, and -0.781, respectively, all P<0.05). After intervention optimization based on feedback from wave 1, participants in wave 2 (n=8) showed an increase in walking time (2.2±0.8 to 3.0±1.3 h/day, P=0.001) and attenuated cytokine production of IL-6, IL-8, and IL-10 (all P<0.05). Glycolysis (P=0.08) and maximal OXPHOS (P=0.04) of peripheral blood mononuclear cells decreased after intervention. Lower IL-6 concentrations (P=0.06) and monocyte percentages (P<0.05), but no changes in monocyte subsets were found. Conclusions Successfully improving walking time shifts innate immune function towards a less proinflammatory state, characterized by a lower capacity to produce inflammatory cytokines, in individuals with increased cardiovascular risk.y cytokines, in individuals with increased cardiovascular risk.)
Poles 2021 Front Immunol + (Background and aims: The systemic host res … Background and aims: The systemic host response in sepsis is frequently accompanied by central nervous system (CNS) dysfunction. Evidence suggests that excessive formation of neutrophil extracellular traps (NETs) can increase the permeability of the blood-brain barrier (BBB) and that the evolving mitochondrial damage may contribute to the pathogenesis of sepsis-associated encephalopathy. Kynurenic acid (KYNA), a metabolite of tryptophan catabolism, exerts pleiotropic cell-protective effects under pro-inflammatory conditions. Our aim was to investigate whether exogenous KYNA or its synthetic analogues SZR-72 and SZR-104 affect BBB permeability secondary to NET formation and influence cerebral mitochondrial disturbances in a clinically relevant rodent model of intraabdominal sepsis.Methods: Sprague-Dawley rats were subjected to fecal peritonitis (0.6 g kg-1 ip) or a sham operation. Septic animals were treated with saline or KYNA, SZR-72 or SZR-104 (160 µmol kg-1 each ip) 16h and 22h after induction. Invasive monitoring was performed on anesthetized animals to evaluate respiratory, cardiovascular, renal, hepatic and metabolic parameters to calculate rat organ failure assessment (ROFA) scores. NET components (citrullinated histone H3 (CitH3); myeloperoxidase (MPO)) and the NET inducer IL-1β, as well as IL-6 and a brain injury marker (S100B) were detected from plasma samples. After 24h, leukocyte infiltration (tissue MPO) and mitochondrial complex I- and II-linked (CI-CII) oxidative phosphorylation (OXPHOS) were evaluated. In a separate series, Evans Blue extravasation and the edema index were used to assess BBB permeability in the same regions.Results: Sepsis was characterized by significantly elevated ROFA scores, while the increased BBB permeability and plasma S100B levels demonstrated brain damage. Plasma levels of CitH3, MPO and IL-1β were elevated in sepsis but were ameliorated by KYNA and its synthetic analogues. The sepsis-induced deterioration in tissue CI-CII-linked OXPHOS and BBB parameters as well as the increase in tissue MPO content were positively affected by KYNA/KYNA analogues.Conclusion: This study is the first to report that KYNA and KYNA analogues are potential neuroprotective agents in experimental sepsis. The proposed mechanistic steps involve reduced peripheral NET formation, lowered BBB permeability changes and alleviation of mitochondrial dysfunction in the CNS.n of mitochondrial dysfunction in the CNS.)
Distefano 2012 Abstract IOC68 + (Background: Aging is associated with reduc … Background: Aging is associated with reductions in skeletal muscle mitochondria function as evidenced by a decreased capacity for ATP production and mitochondrial protein content [1,2,3]. Aging is also associated with changes in body composition, including increased adiposity, and a loss of aerobic fitness. Both are factors that confound an examination of the relationship between mitochondrial function and aging per se. The objective of this study was to determine whether the respiratory properties of permeabilized skeletal muscle fibers are altered with chronological age, or more related to age associated changes in adiposity and aerobic fitness.Methods: A total of 63 participants were assigned to one of the following groups: Young (Y, 26.9 ± 0.9 yrs, ''n''=30), Middle-aged (M, 41.2 ± 2.4 yrs, ''n''=13), or Elderly (77.7 ± 1.1 yrs, ''n''=20). Following an overnight fast, a percutaneous muscle biopsy of vastus lateralis was obtained. Maximal coupled (St.''P''), maximal non-coupled (St.''E''), and LEAK state (St.''L'') respiration was determined in saponin permeabilized muscle fiber bundles using high-resolution respirometry. ''V''O2peak was determined by a graded exercise test. Total body fat and fat free mass were assessed by whole body DEXA.Results: The Y group had significantly greater levels of St.''P'' respiration (220 ± 15 pmol O2 s-1mg-1) compared to M (166 ± 13 pmol O2 s-1mg-1, ''P'' = 0.02) and O groups (170 ± 13 pmol O2 s-1mg-1, ''P'' = 0.014). There was no difference in St.''P'' respiration between M and O groups. Similar group differences were also observed for St.''E'' and St.''L'' respiration. The Y group exhibited a higher ''V''O2peak (46 ± 2.9 ml min-1kg-1) compared to M (28 ± 1.8 ml min-1kg-1, ''P''<0.01) and O (21 ± 2.2 ml min-1kg-1, ''P''<0.01) groups. When the three groups were combined, St.''P'' respiration was positively correlated with ''V''O2peak (''R'' = 0.631, ''P''<0.01), and negatively correlated with age (''R'' = -0.324, ''P'' = 0.01), BMI (''R'' =-0.371, ''P''<0.01), fasting glucose (''R'' = -0.252, ''P'' = 0.047), and fat mass (''R'' = -0.516, ''P'' = <0.01).Conclusions: Our data suggest that age related changes in body composition and aerobic fitness may be more important to mitochondrial dysfunction than chronological age per se.References: 1. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI (2003) Mitochondrial dysfunction in the elderly: Possible role in insulin resistance. Science 300: 1140-1142.2. Conley KE, Jubrias SA, Esselman PC (2000) Oxidative capacity and ageing in human muscle. J Physiol 526: 203-210.3. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS (2005) Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A 102: 5618-5623.idative capacity and ageing in human muscle. J Physiol 526: 203-210. 3. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS (2005) Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A 102: 5618-5623.)
Haslam 2007 Obes Rev + (Background: Although there have been major … Background: Although there have been major advances in the study of obesity, Aibo clearly demonstrates that the one thing the battle against obesity does not need is new scientific invention. Reaven’s utterances proved pivotal, and nothing since has carried the gravitas of his proclamation. Aibo, on the other hand, will be consigned to history’s waste bin. Uniquely among chronic diseases, lack of scientific knowledge is not a barrier to the successful treatment of a person who is obese. Whereas cancer treatment requires new drugs and heart disease updated techniques, obesity is different. We already know enough about the causes and how to manage it by diet, activity, drugs and surgery. The history of obesity is a history of failure. Looking back in time, however, gives us many insights as to treatment in the future. Obesity in history: Obesity is changing, but its origins can be traced back 30 000 years, to our prehistoric ancestors. Survival of the fittest dictated that individuals who stored energy in the most efficient way would survive the inevitable fast and famine that would follow times of plenty. This has been attributed to the ‘thrifty gene’ (although no such individual gene exists), ensuring the continued dominance of our hunter–gatherer predecessors. But natural selection has turned on us. Life now favours inefficient phenotypes who fail to store energy in adipose depots, while those who lay down fat in the abdomen are condemned to premature death. To fight obesity, we are flying in the face of evolution and instinct, consciously countermanding the urge to eat for survival, and be as inactive as possible in order to conserve energy.The situation today: The UK is now in the throes of an obesity epidemic, and risks following in the footsteps of America, where obesity has already delivered an epidemic of diabetes. Writers and physicians over many centuries have dedicated their life’s work to teach the preservation of health, and warn of the dire consequences of ignoring good diet and activity. However, their wisdom has been disregarded. Life expectancy has been improving for centuries; advances in hygiene, science, public health and medicine have allowed longer and more productive lives. Obesity threatens to undo many of these gains. Could it even herald a reduction in life expectancy in coming generations? Instead of spending precious resources inventing novel scientific gadgets, the works of our forefathers should be revisited, and the simple lessons learned from history used to once again prioritize the preservation of health.ain prioritize the preservation of health.)
Pühringer 2021 High Alt Med Biol + (Background: Altitude exposure reduces maxi … Background: Altitude exposure reduces maximal oxygen uptake (''V''O2max). Usually, the reduction is not restored with acclimatization (at least at altitudes above 2500 m) and is more pronounced in highly trained athletes compared to nonathletes. It still remains to be elucidated whether these also apply for well-acclimatized individuals (i.e., mountain guides) acutely exposed to moderate altitude (i.e., 2000 m). Methods: A total of 128 acclimatized male mountain guides of the Austrian armed forces (42.2 ± 7.0 years, 177.8 ± 5.6 cm, 77.2 ± 7.0 kg) of different fitness levels performed 2 incremental cycle ergometer tests 1 week apart, one at low (600 m) and one at moderate altitude (2000 m). Oxygen uptake, heart rate (HR), and lactate concentration were measured during the tests. Results: In acclimatized mountain guides, lower baseline ''V''O2max levels were associated with better preservation of ''V''O2max at moderate altitude compared to higher levels. At moderate altitude, physiological responses (HR and blood lactate at 100 W) at a submaximal exercise intensity of 100 W remained unchanged or were even slightly reduced in both groups. Conclusions: Long-term acclimatization to moderate altitude may prevent the ''V''O2max decline at a moderate altitude of 2 000 m particularly in subjects with lower ''V''O2max levels, that is, below the 80th percentile (for age and sex). In people with higher fitness levels, ''V''O2max may still be negatively affected. These results are of practical relevance, for example, for workers, athletes, ski and mountain guides, military staff, or rescue staff who regularly or continuously have to perform at moderate altitude.e of practical relevance, for example, for workers, athletes, ski and mountain guides, military staff, or rescue staff who regularly or continuously have to perform at moderate altitude.)
Reiss 2022 Exp Gerontol + (Background: Alzheimer's disease (AD) is th … Background: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell.Methods: Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD.Results: This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD.Conclusions: There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.s to achieve breakthroughs in treating AD.)
Wider 2023 Crit Care + (Background: Brain injury is a leading caus … Background: Brain injury is a leading cause of morbidity and mortality in patients resuscitated from cardiac arrest. Mitochondrial dysfunction contributes to brain injury following cardiac arrest; therefore, therapies that limit mitochondrial dysfunction have the potential to improve neurological outcomes. Generation of reactive oxygen species (ROS) during ischemia-reperfusion injury in the brain is a critical component of mitochondrial injury and is dependent on hyperactivation of mitochondria following resuscitation. Our previous studies have provided evidence that modulating mitochondrial function with specific near-infrared light (NIR) wavelengths can reduce post-ischemic mitochondrial hyperactivity, thereby reducing brain injury during reperfusion in multiple small animal models.Methods: Isolated porcine brain cytochrome c oxidase (COX) was used to investigate the mechanism of NIR-induced mitochondrial modulation. Cultured primary neurons from mice expressing mitoQC were utilized to explore the mitochondrial mechanisms related to protection with NIR following ischemia-reperfusion. Anesthetized pigs were used to optimize the delivery of NIR to the brain by measuring the penetration depth of NIR to deep brain structures and tissue heating. Finally, a model of out-of-hospital cardiac arrest with CPR in adult pigs was used to evaluate the translational potential of NIR as a noninvasive therapeutic approach to protect the brain after resuscitation.Results: Molecular evaluation of enzyme activity during NIR irradiation demonstrated COX function was reduced in an intensity-dependent manner with a threshold of enzyme inhibition leading to a moderate reduction in activity without complete inhibition. Mechanistic interrogation in neurons demonstrated that mitochondrial swelling and upregulation of mitophagy were reduced with NIR treatment. NIR therapy in large animals is feasible, as NIR penetrates deep into the brain without substantial tissue heating. In a translational porcine model of CA/CPR, transcranial NIR treatment for two hours at the onset of return of spontaneous circulation (ROSC) demonstrated significantly improved neurological deficit scores and reduced histologic evidence of brain injury after resuscitation from cardiac arrest.Conclusions: NIR modulates mitochondrial function which improves mitochondrial dynamics and quality control following ischemia/reperfusion. Noninvasive modulation of mitochondria, achieved by transcranial treatment of the brain with NIR, mitigates post-cardiac arrest brain injury and improves neurologic functional outcomes.d improves neurologic functional outcomes.)
Serafim 2021 Eur J Clin Invest + (Background: Changes in the nutritional env … Background: Changes in the nutritional environment in utero induced by maternal obesity (MO) lead to foetal metabolic dysfunction predisposing offspring to later-life metabolic diseases. Since mitochondria play a crucial role in hepatic metabolism and function, we hypothesized that MO prior to conception and throughout pregnancy programmes foetal sheep liver mitochondrial phenotype.Material and methods: Ewes ate an obesogenic diet (150% requirements; MO), or 100% requirements (CTR), from 60 days prior to conception. Foetal livers were removed at 0.9 gestation. We measured foetal liver mitochondrial DNA copy number, activity of superoxide dismutase, cathepsins B and D and selected protein content, total phospholipids and cardiolipin and activity of mitochondrial respiratory chain complexes.Results: A significant decrease in activities of mitochondrial complexes I, II-III and IV, but not aconitase, was observed in MO. In the antioxidant machinery, there was a significant increase in activity of total superoxide dismutase (SOD) and SOD2 in MO. However, no differences were found regarding autophagy-related protein content (p62, beclin-I, LC3-I, LC3-II and Lamp2A) and cathepsin B and D activities. A 21.5% decrease in total mitochondrial phospholipid was observed in MO.Conclusions: The data indicate that MO impairs foetal hepatic mitochondrial oxidative capacity and affects total mitochondrial phospholipid content. In addition, MO affects the regulation of foetal liver redox pathways, indicating metabolic adaptations to the higher foetal lipid environment. Consequences of in utero programming of foetal hepatic metabolism may persist and compromise mitochondrial bioenergetics in later life, and increase susceptibility to metabolic diseases.ease susceptibility to metabolic diseases.)
Picard 2018 Biol Psychiatry + (Background: Chronic life stress, such as t … Background: Chronic life stress, such as the stress of caregiving, can promote pathophysiology, but the underlying cellular mechanisms are not well understood. Chronic stress may induce recalibrations in mitochondria leading to changes either in mitochondrial content per cell, or in mitochondrial functional capacity (i.e., quality).Methods: Here we present a functional index of mitochondrial health (MHI) for human leukocytes that can distinguish between these two possibilities. The MHI integrates nuclear and mitochondrial DNA-encoded respiratory chain enzymatic activities and mitochondrial DNA copy number. We then use the MHI to test the hypothesis that daily emotional states and caregiving stress influence mitochondrial function by comparing healthy mothers of a child with an autism spectrum disorder (high-stress caregivers, ''n'' = 46) with mothers of a neurotypical child (control group, ''n'' = 45).Results: The MHI outperformed individual mitochondrial function measures. Elevated positive mood at night was associated with higher MHI, and nightly positive mood was also a mediator of the association between caregiving and MHI. Moreover, MHI was correlated to positive mood on the days preceding, but not following the blood draw, suggesting for the first time in humans that mitochondria may respond to proximate emotional states within days. Correspondingly, the caregiver group, which had higher perceived stress and lower positive and greater negative daily affect, exhibited lower MHI. This effect was not explained by a mismatch between nuclear and mitochondrial genomes.Conclusions: Daily mood and chronic caregiving stress are associated with mitochondrial functional capacity. Mitochondrial health may represent a nexus between psychological stress and health.s between psychological stress and health.)
Bhatraju 2020 N Engl J Med + (Background: Community transmission of coro … Background: Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020.Methods: We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up.Results: We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63 % were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50 % of patients had fever on admission, and 58 % had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75 % (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU.Conclusions: During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.).ed by the National Institutes of Health.).)
Catania 2019 Orphanet J Rare Dis + (Background: Complex I (CI or NADH:ubiquino … Background: Complex I (CI or NADH:ubiquinone oxidoreductase) deficiency is the most frequent cause of mitochondrial respiratory chain defect. Successful attempts to rescue CI function by introducing an exogenous NADH dehydrogenase, such as the NDI1 from Saccharomyces cerevisiae (ScNDI1), have been reported although with drawbacks related to competition with CI. In contrast to ScNDI1, which is permanently active in yeast naturally devoid of CI, plant alternative NADH dehydrogenases (NDH-2) support the oxidation of NADH only when the CI is metabolically inactive and conceivably when the concentration of matrix NADH exceeds a certain threshold. We therefore explored the feasibility of CI rescue by NDH-2 from Arabidopsis thaliana (At) in human CI defective fibroblasts.Results: We showed that, other than ScNDI1, two different NDH-2 (AtNDA2 and AtNDB4) targeted to the mitochondria were able to rescue CI deficiency and decrease oxidative stress as indicated by a normalization of SOD activity in human CI-defective fibroblasts. We further demonstrated that when expressed in human control fibroblasts, AtNDA2 shows an affinity for NADH oxidation similar to that of CI, thus competing with CI for the oxidation of NADH as opposed to our initial hypothesis. This competition reduced the amount of ATP produced per oxygen atom reduced to water by half in control cells.Conclusions: In conclusion, despite their promising potential to rescue CI defects, due to a possible competition with remaining CI activity, plant NDH-2 should be regarded with caution as potential therapeutic tools for human mitochondrial diseases.ic tools for human mitochondrial diseases.)
Furihata 2021 BMC Pharmacol Toxicol + (Background: Doxorubicin (DOX) is widely us … Background: Doxorubicin (DOX) is widely used as an effective chemotherapeutic agent for cancers; however, DOX induces cardiac toxicity, called DOX-induced cardiomyopathy. Although DOX-induced cardiomyopathy is known to be associated with a high cumulative dose of DOX, the mechanisms of its long-term effects have not been completely elucidated. Pioglitazone (Pio) is presently contraindicated in patients with symptomatic heart failure owing to the side effects. The concept of drug repositioning led us to hypothesize the potential effects of Pio as a premedication before DOX treatment, and to analyze this hypothesis in mice.Methods: First, for the hyperacute (day 1) and acute (day 7) DOX-induced dysfunction models, mice were fed a standard diet with or without 0.02% (wt/wt) Pio for 5 days before DOX treatment (15 mg/kg body weight [BW] via intraperitoneal [i.p.] administration). The following 3 treatment groups were analyzed: standard diet + vehicle (Vehicle), standard diet + DOX (DOX), and Pio + DOX. Next, for the chronic model (day 35), the mice were administrated DOX once a week for 5 weeks (5 mg/kg BW/week, i.p.).Results: In the acute phase after DOX treatment, the percent fractional shortening of the left ventricle (LV) was significantly decreased in DOX mice. This cardiac malfunction was improved in Pio + DOX mice. In the chronic phase, we observed that LV function was preserved in Pio + DOX mice.Conclusions: Our findings may provide a new pathophysiological explanation by which Pio plays a role in the treatment of DOX-induced cardiomyopathy, but the molecular links between Pio and DOX-induced LV dysfunction remain largely elusive.ced LV dysfunction remain largely elusive.)
Zuccolotto-dos-Reis 2021 Eur J Clin Invest + (Background: Freezing human biopsies is com … Background: Freezing human biopsies is common in clinical practice for storage. However, this technique disrupts mitochondrial membranes, hampering further analyses of respiratory function. To contribute to laboratorial diagnosis of mitochondrial diseases, this study sought to develop a respirometry approach using O2k (Oroboros Ins.) to measure the whole electron transport chain (ETC) activity in homogenates of frozen skeletal muscle biopsies.Patients and methods: We enrolled 16 patients submitted to muscle biopsy in the process of routine diagnostic investigation: four with mitochondrial disease and severe mitochondrial dysfunction; seven with exercise intolerance and multiple deletions of mitochondrial DNA, presenting mild to moderate mitochondrial dysfunction; five without mitochondrial disease, as controls. Whole homogenates of muscle fragments were prepared using grinder-type equipment. O2 consumption rates were normalized using citrate synthase activity.Results: Transmission electron microscopy confirmed mitochondrial membrane discontinuation, indicating increased permeability of mitochondrial membranes in homogenates from frozen biopsies. O2 consumption rates in the presence of acetyl-CoA lead to maximum respiratory rates sensitive to rotenone, malonate and antimycin. This protocol of acetyl-CoA-driven respiration (ACoAR), applied in whole homogenates of frozen muscle, was sensitive enough to identify ETC abnormality, even in patients with mild to moderate mitochondrial dysfunction. We demonstrated adequate repeatability of ACoAR and found significant correlation between O2 consumption rates and enzyme activity assays of individual ETC complexes.Conclusions: We present preliminary data on a simple, low cost and reliable procedure to measure respiratory function in whole homogenates of frozen skeletal muscle biopsies, contributing to diagnosis of mitochondrial diseases in humans.Keywords: acetyl-CoA-driven respiration; electron transport chain; frozen skeletal muscle biopsy; high-resolution respirometry; mitochondrial diseases; oxygen consumption rate.ondrial diseases; oxygen consumption rate.)
Guralnik 1995 N Engl J Med + (Background: Functional assessment is an im … Background: Functional assessment is an important part of the evaluation of elderly persons. We conducted this study to determine whether objective measures of physical function can predict subsequent disability in older persons.Methods: This prospective cohort study included men and women 71 years of age or older who were living in the community, who reported no disability in the activities of daily living, and who reported that they were able to walk one-half mile (0.8 km) and climb stairs without assistance. The subjects completed a short battery of physical-performance tests and participated in a follow-up interview four years later. The tests included an assessment of standing balance, a timed 8-ft (2.4-m) walk at a normal pace, and a timed test of five repetitions of rising from a chair and sitting down.Results: Among the 1122 subjects who were not disabled at base line and who participated in the four-year follow-up, lower scores on the base-line performance tests were associated with a statistically significant, graduated increase in the frequency of disability in the activities of daily living and mobility-related disability at follow-up. After adjustment for age, sex, and the presence of chronic disease, those with the lowest scores on the performance tests were 4.2 to 4.9 times as likely to have disability at four years as those with the highest performance scores, and those with intermediate performance scores were 1.6 to 1.8 times as likely to have disability.Conclusions: Among nondisabled older persons living in the community, objective measures of lower-extremity function were highly predictive of subsequent disability. Measures of physical performance may identify older persons with a preclinical stage of disability who may benefit from interventions to prevent the development of frank disability.event the development of frank disability.)
Lin 2017 Neuro Oncol + (Background: Glioma is the most common form … Background: Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are thought to primarily metabolize glucose for energy production; however, the reliance upon glycolysis has recently been called into question. In this study, we aimed to identify the metabolic fuel requirements of human glioma cells.Methods: We used database searches and tissue culture resources to evaluate genotype and protein expression, tracked oxygen consumption rates to study metabolic responses to various substrates, performed histochemical techniques and fluorescence-activated cell sorting-based mitotic profiling to study cellular proliferation rates, and employed an animal model of malignant glioma to evaluate a new therapeutic intervention.Results: We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma.Conclusions: Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this metabolic pathway reduces energy production and cellular proliferation in glioma cells. The drug etomoxir may provide therapeutic benefit to patients with malignant glioma. In addition, the expression of fatty acid oxidation enzymes may provide prognostic indicators for clinical practice.ognostic indicators for clinical practice.)
Agrillo 2020 PLOS ONE + (Background: Humans and non-human animals s … Background: Humans and non-human animals share an approximate non-verbal system for representing and comparing numerosities that has no upper limit and for which accuracy is dependent on the numerical ratio. Current evidence indicates that the mechanism for keeping track of individual objects can also be used for numerical purposes; if so, its accuracy will be independent of numerical ratio, but its capacity is limited to the number of items that can be tracked, about four. There is, however, growing controversy as to whether two separate number systems are present in other vertebrate species.Methodology/Principal Findings: In this study, we compared the ability of undergraduate students and guppies to discriminate the same numerical ratios, both within and beyond the small number range. In both students and fish the performance was ratio-independent for the numbers 1–4, while it steadily increased with numerical distance when larger numbers were presented.Conclusions/Significance: Our results suggest that two distinct systems underlie quantity discrimination in both humans and fish, implying that the building blocks of uniquely human mathematical abilities may be evolutionarily ancient, dating back to before the divergence of bony fish and tetrapod lineages.rgence of bony fish and tetrapod lineages.)
Kaczynski FENS Forum 2010 + (Background: L-arginine (2-amino-5-guanidin … Background: L-arginine (2-amino-5-guanidino-pentanoic acid) is an important amino acid for birds, carnivores and mammals. Its metabolism is complex and is only partially known. L-arginine is a substrate for nitric oxide (NO) which penetrates freely across cell membranes. The enhanced generation of NO may reduce necrosis and apoptosis in ischemia/reperfusion-induced injury in ratliver. NO donors also protect the ischemic heart from apoptosis and mitochondrial dysfunction via PKG-mediated blockage of mitochondrial permeability transition pores and subsequenced cytochrome ''c'' release. It is anticipated that NO through cGMP-dependent mechanisms can activatesurvival paths in hippocampal neurons and prevent apoptosis.Aims: The study of the mitochondria-related antiapoptotic influence of L-arginine against proapoptotic, proinflammatory, and metabolic stressor staurosporine in human glioblastoma LN-18 (brain cell line).Methods: The cultured glioblastoma LN-18 cells were preincubated with L-arginine (L-arg; 0.1, 0.3 or 1 mM) for 24 hours and were challenged with staurosporine (STS; 0.025 microM) for the last four hours of incubation. Measurement of the mitochondrial respiration rates was performed using Oxygraph-2k (OROBOROS®). The ATP generation was followed by using luminescence method withLuciferase/Luciferine (ATP Lite, Parkin Elmer) commercial kits. Additionally the changes in the internal mitochondrial membrane potential by the high-content cell analysis confocal fluorescent microscopy which allows prolonged imaging of live cells in controlled environment (BD Pathway 855 Bioimager) are presently performed with the usage of TMRM (for active mitochondria staining) andHoechst (for nucleus staining).Results: L-arginine per se at 0.3 mM to 1 mM increased ATP generation, but this effect was reduced by the presence of the proapoptotic staurosporine.Conclusions: L-arginine seems to increase ATP generation in LN-18 cells, however this effect could not overcome the influence of staurosporine. The possible influence on mitochondrial membrane potential will be presented.Supported by the Polish-Norwegian Research Found no. PNRF-104-Al-1/07.egian Research Found no. PNRF-104-Al-1/07.)
Kaczynski 2010 FENS Abstr + (Background: L-arginine (2-amino-5-guanidin … Background: L-arginine (2-amino-5-guanidino-pentanoic acid) is an important amino acid for birds, carnivores and mammals. Its metabolism is complex and is only partially known. L-arginine is a substrate for nitric oxide (NO) which penetrates freely across cell membranes. The enhanced generation of NO may reduce necrosis and apoptosis in ischemia/reperfusion-induced injury in ratliver. NO donors also protect the ischemic heart from apoptosis and mitochondrial dysfunction via PKG-mediated blockage of mitochondrial permeability transition pores and subsequenced cytochrome c release. It is anticipated that NO through cGMP-dependent mechanisms can activatesurvival paths in hippocampal neurons and prevent apoptosis.Aims: The study of the mitochondria-related antiapoptotic influence of L-arginine against proapoptotic, proinflammatory, and metabolic stressor staurosporine in human glioblastoma LN-18 (brain cell line).Methods: The cultured glioblastoma LN-18 cells were preincubated with L-arginine (L-arg; 0.1, 0.3 or 1 mM) for 24 hours and were challenged with staurosporine (STS; 0.025 microM) for the last four hours of incubation. Measurement of the mitochondrial respiration rates was performed usingOxygraph-2k (OROBOROS®). The ATP generation was followed by using luminescence method with Luciferase/Luciferine (ATP Lite, Parkin Elmer) commercial kits. Additionally the changes in the internal mitochondrial membrane potential by the high-content cell analysis confocal fluorescent microscopy which allows prolonged imaging of live cells in controlled environment (BD Pathway 855Bioimager) are presently performed with the usage of TMRM (for active mitochondria staining) and Hoechst (for nucleus staining).Results: L-arginine per se at 0.3 mM to 1 mM increased ATP generation, but this effect was reduced by the presence of the proapoptotic staurosporine.Conclusions: L-arginine seems to increase ATP generation in LN-18 cells, however this effect could not overcome the influence of staurosporine. The possible influence on mitochondrial membrane potential will be presented.rial membrane potential will be presented.)
Petrilli 2020 medRxiv + (Background: Little is known about factors … Background: Little is known about factors associated with hospitalization and critical illness in Covid-19 positive patients. Methods: We conducted a cross-sectional analysis of all patients with laboratory-confirmed Covid-19 treated at a single academic health system in New York City between March 1, 2020 and April 2, 2020, with follow up through April 7, 2020. Primary outcomes were hospitalization and critical illness (intensive care, mechanical ventilation, hospice and/or death). We conducted multivariable logistic regression to identify risk factors for adverse outcomes, and maximum information gain decision tree classifications to identify key splitters. Results: Among 4,103 Covid-19 patients, 1,999 (48.7 %) were hospitalized, of whom 981/1,999 (49.1 %) have been discharged home, and 292/1,999 (14.6 %) have died or were discharged to hospice. Of 445 patients requiring mechanical ventilation, 162/445 (36.4 %) have died. Strongest hospitalization risks were age ≥75 years (OR 66.8, 95 % CI, 44.7-102.6), age 65-74 (OR 10.9, 95 % CI, 8.35-14.34), BMI>40 (OR 6.2, 95 % CI, 4.2-9.3), and heart failure (OR 4.3 95 % CI, 1.9-11.2). Strongest critical illness risks were admission oxygen saturation <88 % (OR 6.99, 95 % CI 4.5-11.0), d-dimer>2500 (OR 6.9, 95 % CI, 3.2-15.2), ferritin >2500 (OR 6.9, 95 % CI, 3.2-15.2), and C-reactive protein (CRP) >200 (OR 5.78, 95 % CI, 2.6-13.8). In the decision tree for admission, the most important features were age >65 and obesity; for critical illness, the most important was SpO2<88, followed by procalcitonin >0.5, troponin <0.1 (protective), age >64 and CRP>200. Conclusions: Age and comorbidities are powerful predictors of hospitalization; however, admission oxygen impairment and markers of inflammation are most strongly associated with critical illness.markers of inflammation are most strongly associated with critical illness.)
Stensvold 2012 Metab Syndr Relat Disord + (Background: Metabolic syndrome is associat … Background: Metabolic syndrome is associated with chronic low-grade inflammation, a condition thought to play a key role in the pathogenesis of the syndrome. Among a number of proinflammatory cytokines, interleukin-18 (IL-18) seems to be the best marker for inflammation among people with metabolic syndrome. The aim of this study was to examine the effect of aerobic training versus strength training on circulating IL-18 and other proinflammatory markers in people with metabolic syndrome. Methods: Thirty-one inactive men and women with metabolic syndrome were randomized to either high-intensity aerobic interval training ('''AIT''', ''n''=11), strength training ('''ST''', ''n''=10), or a control group (''n''=10). Exercise training was carried out three times per week for 12 weeks. Serum insulin, high-sensitivity C-reactive protein (hsCRP), IL-18, IL-6, and tumor necrosis factor-α (TNF-α) were measured before and after the intervention. Results: Serum IL-18 was reduced by 43% after AIT (''P''<0.001). Although there was no change in TNF-α from baseline after AIT, the levels were lower compared to the ST (''P''=0.032) and control groups (''P''=0.039) after the intervention. Total body fat was reduced after AIT (from 33.9±7.3% to 32.2±7.9%, ''P''<0.001) and ST (from 31.2±3.9% to 29.7±3.4%, ''P''=0.025). There were no changes in serum IL-6, insulin, or hsCRP within or between the groups. Conclusion: Both ST and AIT reduced fat mass. However, only the latter intervention was associated with a more favorable inflammatory status among people with metabolic syndrome. Clinical Trial Registration Information: http://clinicaltrials.gov/show/NCT00986024/ion: http://clinicaltrials.gov/show/NCT00986024/)
Huete-Ortega 2018 Biotechnol Biofuels + (Background: Microalgae accumulate lipids w … Background: Microalgae accumulate lipids when exposed to stressful conditions such as nutrient limitation that can be used to generate biofuels. Nitrogen limitation or deprivation is a strategy widely employed to elicit this response. However, this strategy is associated with a reduction in the microalgal growth, leading to overall poor lipid productivities. Here, we investigated the combined effect of a reduced source of nitrogen (ammonium) and super-saturating light intensities on the growth and induction of lipid accumulation in two model but diverse microalgal species, Phaeodactylum tricornutum and Nannochloropsis oceanica. We hypothesized that the lower energy cost of assimilating ammonium would allow the organisms to use more reductant power for lipid biosynthesis without compromising growth and that this would be further stimulated by the effect of high light (1000 µmol m-2 s-1) stress. We studied the changes in growth and physiology of both species when grown in culture media that either contained nitrate or ammonium as the nitrogen source, and an additional medium that contained ammonium with tungsten in place of molybdenum and compared this with growth in media without nitrogen. We focused our investigation on the early stages of exposure to the treatments to correspond to events relevant to induction of lipid accumulation in these two species.Results: At super-saturating light intensities, lipid productivity in P. tricornutum increased twofold when grown in ammonium compared to nitrogen free medium that increased further when tungsten was present in the medium in place of molybdenum. Conversely, N. oceanica growth and physiology was not compromised by the high light intensities used, and the use of ammonium had a negative effect on the lipid productivity, which was even more marked when tungsten was present.Conclusions: Whilst the use of ammonium and super-saturating light intensities in P. tricornutum was revealed to be a good strategy for increasing lipid biosynthesis, no changes in the lipid productivity of N. oceanica were observed, under these conditions. Both results provide relevant direction for the better design of processes to produce biofuels in microalgae by manipulating growth conditions without the need to subject them to genetic engineering manipulation. them to genetic engineering manipulation.)
Szczerbinski 2021 Cells + (Background: Mitochondrial dysfunction has … Background: Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes, but its contribution to the early stages of dysglycemia remains poorly understood. By collecting a high-resolution stage-based spectrum of dysglycemia, our study fills this gap by evaluating derangement in both the function and quantity of mitochondria. We sampled mitochondria in skeletal muscle and subcutaneous adipose tissues of subjects with progressive advancement of dysglycemia under a three-month exercise intervention. Methods: We measured clinical metabolic parameters and gathered skeletal muscle and adipose tissue biopsies before and after the three-month exercise intervention. We then assayed the number of mitochondria via citrate synthase (CS) activity and functional parameters with high-resolution respirometry. Results: In muscle, there were no differences in mitochondrial quantity or function at baseline between normoglycemics and prediabetics. However, the intervention caused improvement in CS activity, implying an increase in mitochondrial quantity. By contrast in adipose tissue, baseline differences in CS activity were present, with the lowest CS activity coincident with impaired fasting glucose and impaired glucose tolerance (IFG + IGT). Finally, CS activity, but few of the functional metrics, improved under the intervention. Conclusions: We show that in prediabetes, no differences in the function or amount of mitochondria (measured by CS activity) in skeletal muscle are apparent, but in adipose tissue of subjects with IFG + IGT, a significantly reduced activity of CS was observed. Finally, metabolic improvements under the exercise correlate to improvements in the amount, rather than function, of mitochondria in both tissues.function, of mitochondria in both tissues.)
Zhang 2021 PLOS ONE + (Background: Mitochondrial dysfunction is i … Background: Mitochondrial dysfunction is involved in many complex diseases. Efficient and accurate evaluation of mitochondrial functionality is crucial for understanding pathology as well as facilitating novel therapeutic developments. As a popular platform, Seahorse extracellular flux (XF) analyzer is widely used for measuring mitochondrial oxygen consumption rate (OCR) in living cells. A hidden feature of Seahorse XF OCR data is that it has a complex data structure, caused by nesting and crossing between measurement cycles, wells and plates. Surprisingly, statistical analysis of Seahorse XF data has not received sufficient attention, and current methods completely ignore the complex data structure, impairing the robustness of statistical inference.Results: To rigorously incorporate the complex structure into data analysis, here we developed a Bayesian hierarchical modeling framework, OCRbayes, and demonstrated its applicability based on analysis of published data sets.Conclusions: We showed that OCRbayes can analyze Seahorse XF OCR experimental data derived from either single or multiple plates. Moreover, OCRbayes has potential to be used for diagnosing patients with mitochondrial diseases.sing patients with mitochondrial diseases.)
Besancon 2020 Res Integr Peer Rev + (Background: Our aim is to highlight the be … Background: Our aim is to highlight the benefits and limitations of open and non-anonymized peer review. Our argument is based on the literature and on responses to a survey on the reviewing process of alt.chi, a more or less open review track within the so-called Computer Human Interaction (CHI) conference, the predominant conference in the field of human-computer interaction. This track currently is the only implementation of an open peer review process in the field of human-computer interaction while, with the recent increase in interest in open scientific practices, open review is now being considered and used in other fields.Methods: We ran an online survey with 30 responses from alt.chi authors and reviewers, collecting quantitative data using multiple-choice questions and Likert scales. Qualitative data were collected using open questions.Results: Our main quantitative result is that respondents are more positive to open and non-anonymous reviewing for alt.chi than for other parts of the CHI conference. The qualitative data specifically highlight the benefits of open and transparent academic discussions. The data and scripts are available on https://osf.io/vuw7h/, and the figures and follow-up work on http://tiny.cc/OpenReviews.Conclusion: While the benefits are quite clear and the system is generally well-liked by alt.chi participants, they remain reluctant to see it used in other venues. This concurs with a number of recent studies that suggest a divergence between support for a more open review process and its practical implementation. process and its practical implementation.)
Qingxian 2020 Lancet + (Background: Patients with obesity are at i … Background: Patients with obesity are at increased risk of exacerbations from viral respiratory infections. However, the association of obesity with severity of corona virus disease 2019 (COVID-19) is unclear. We hereby examined this association using data from the only referral hospital in Shenzhen, China.Methods: 383 COVID-19 patients admitted from 11 January to 16 February 2020 in the Third People’s Hospital of Shenzhen, China were included. Underweight was defined by body mass index (BMI) lower than 18·5 kg/m2, normal weight by 18·5-23·9 kg/m2 , overweight by 24·0- 27·9 kg/m2 and obesity as ≥28 kg/m2.Findings: Of them, 53·1 % were normal weight, 4·2 % were underweight, 32·0 % were overweight, and 10·7 % were obese. Patients with obesity, versus without, were tended to have cough (''P''=0·03) and fever (''P''=0·06). After adjusting for potential confounders, compared to normal weight, overweight showed 86 % higher, and obesity group showed 2·42-fold higher odds of developing severe pneumonia. Despite a non-significant sex interaction was found (''P''=0·09), the association appeared to be more pronounced in men than in women. The odds ratios (95 % confidence intervals) for severe pneumonia in overweight and obesity was 1·96 (0·78-4·98) and 5·70 (1·83-17·76) in men, and 1·51 (0·57-4·01) and 0·71 (0·07-7·3) in women, respectively.Interpretation: This is the first study showing that obesity, especially in men, significantly increases the risk of developing severe pneumonia in COVID-19 patients. As the 2019n-Cov may continue to spread worldwide, clinicians should maintain a high level of attention in obese patients. Obese patients should be carefully managed with prompt and aggressive treatment.aged with prompt and aggressive treatment.)
Caspi 2020 J Am Heart Assoc + (Background: People with chronic heart fail … Background: People with chronic heart failure (CHF) experience severe skeletal muscle dysfunction, characterized by mitochondrial abnormalities, which exacerbates the primary symptom of exercise intolerance. However, the molecular triggers and characteristics underlying mitochondrial abnormalities caused by CHF remain poorly understood.Methods and Results: We recruited 28 patients with CHF caused by reduced ejection fraction and 9 controls. We simultaneously biopsied skeletal muscle from the pectoralis major in the upper limb and from the vastus lateralis in the lower limb. We phenotyped mitochondrial function in permeabilized myofibers from both sites and followed this by complete RNA sequencing to identify novel molecular abnormalities in CHF skeletal muscle. Patients with CHF presented with upper and lower limb skeletal muscle impairments to mitochondrial function that were of a similar deficit and indicative of a myopathy. Mitochondrial abnormalities were strongly correlated to symptoms. Further RNA sequencing revealed a unique transcriptome signature in CHF skeletal muscle characterized by a novel triad of differentially expressed genes related to deficits in energy metabolism including adenosine monophosphate deaminase 3, pyridine nucleotide‐disulphide oxidoreductase domain 2, and lactate dehydrogenase C.Conclusions: Our data suggest an upper and lower limb metabolic myopathy that is characterized by a unique transcriptome signature in skeletal muscle of humans with CHF.ure in skeletal muscle of humans with CHF.)
Mehta 2008 Chest + (Background: Pulmonary vasoconstriction in … Background: Pulmonary vasoconstriction in response to hypoxia is unusual inasmuch as local exposure of nonpulmonary vasculature to hypoxia results in vasodilation. It has been suggested that pulmonary artery smooth-muscle cells may relax in response to intracellular generation of reactive oxygen species (ROS) and that the production of ROS decreases under hypoxia. However, other workers report increased ROS production in human pulmonary artery smooth-muscle cells (HPASMC) during hypoxia.Methods: Using dihydrodichlorofluorescein diacetate, dihydroethidium, and Amplex Red (Molecular Probes; Eugene, OR), we estimated ROS generation by confluent primary cultures of HPASMC and human coronary artery smooth-muscle cells (HCASMC) under normoxia (20%) and acute hypoxia (5%).Results: All three assay systems showed that HPASMC production of ROS is decreased under hypoxia and to a greater extent than the decrease in ROS production by HCASMC. A substantially greater percentage of normoxic ROS production by HPASMC is mitochondrial (> 60%) compared to HCASMC (< 30%).Conclusions: These results support the conclusion that ROS generation decreases, rather than increases, in HPASMC during hypoxia. However, as ROS production also decreases in HCASMC during hypoxia, the reason for the opposite change in vascular tone is not yet apparent.ite change in vascular tone is not yet apparent.)
Liu 2009 J Biomed Sci + (Background: Reactive oxygen species (ROS) … Background: Reactive oxygen species (ROS) play an important role in aging and age-related diseases such as Parkinson's disease and Alzheimer's disease. Much of the ROS production under conditions of toxic stress is from mitochondria, and multiple antioxidants prevent ROS accumulation. The aim of this study is to examine the specificity of the interaction between the antioxidants and ROS production in stressed cells.Methods: Using fluorescent dyes for ROS detection and mitochondrial inhibitors of known specificities, we studied ROS production under three conditions where ROS are produced by mitochondria: oxidative glutamate toxicity, state IV respiration induced by oligomycin, and tumor necrosis factor-induced cell death.Results: We demonstrated that there are at least four mitochondrial ROS-generating sites in cells, including the flavin mononucleotide (FMN) group of complex I and the three ubiquinone-binding sites in complexes I, II and III. ROS production from these sites is modulated in an insult-specific manner and the sites are differentially accessible to common antioxidants.Conclusion: The inhibition of ROS accumulation by different antioxidants is specific to the site of ROS generation as well as the antioxidant. This information should be useful for devising new interventions to delay aging or treat ROS-related diseases.delay aging or treat ROS-related diseases.)
Pollack 2017 J Gerontol A Biol Sci Med Sci + (Background: Resveratrol, a plant-derived p … Background: Resveratrol, a plant-derived polyphenol, has been reported to improve glucose metabolism and vascular function and to extend life span in animal models, but studies in humans have been inconclusive.Methods: In a randomized, double-blind crossover study, we treated older glucose-intolerant adults (''N'' = 30) with resveratrol (2-3 g/daily) or placebo, each for 6 weeks. A standard mixed-meal test was used to assess insulin sensitivity (Matsuda index) and secretion (C-peptide deconvolution) and vascular function by reactive hyperemia peripheral arterial tonometry. Skeletal muscle samples were obtained for gene expression using RNA-Seq analysis and to assess mitochondrial morphology.Results: There were no changes in glucose tolerance, insulin sensitivity, weight, blood pressure, or lipid profile following resveratrol treatment. Fasting reactive hyperemia index improved with resveratrol (2.02 ± 0.2 vs 1.76 ± 0.02, p = .002). RNA-Seq analysis yielded 140 differentially expressed transcripts (corrected p-value ≤ .05), predominantly associated with mitochondrial genes and noncoding RNA. Ingenuity Pathway Analysis confirmed that mitochondrial dysfunction (p = 2.77 × 10-12) and oxidative phosphorylation (p = 1.41 × 10-11) were the most significantly perturbed pathways. Mitochondrial number, but not size, was increased.Conclusions: Resveratrol treatment of older adults with impaired glucose regulation may have beneficial effects on vascular function, but not glucose metabolism or insulin sensitivity. Changes in gene expression suggest effects similar to those observed with caloric restriction, which has been shown to increase life and health span in animal models, although its significance for humans is uncertain. Future human studies should address the appropriate dose range and low bioavailability of resveratrol.© The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: [email protected].ease e-mail: [email protected].)
Aya 2022 Eur J Pharmacol + (Background: Sodium-glucose cotransporter 2 … Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated to have beneficial effects on HF in large clinical trials; however, the mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms by which empagliflozin, one of SGLT2 inhibitors, affects heart failure.Method and results: Eight-week-old male mice deficient for heart and skeletal muscle-specific manganese superoxide dismutase (MnSOD-cKO mice), a murine model of dilated cardiomyopathy, were given food mixed with or without 10 mg/kg empagliflozin for 7 weeks and evaluated. Both the survival rate and cardiac fibrosis were significantly improved in the empagliflozin group. The capacity for oxidative phosphorylation in cardiac mitochondria was significantly upregulated as measured with Oxygraph-2k respirometer, and blood lactate levels produced by anaerobic metabolism were significantly lower in the empagliflozin group. Energy expenditure was significantly improved in the empagliflozin group, measured by respiratory gas analysis, with a concomitant reduction in serum leptin concentration and increase in food intake. A moderate amount of glucose was excreted in urine in the empagliflozin group; however, the available energy substrate in the body nonetheless expanded because of the much higher caloric intake.Conclusions: We conclude that empagliflozin improved cardiac mitochondrial function and upregulated energy metabolism even in HF in mice. These findings provide novel mechanisms for the beneficial effects of SGLT2 inhibitors on HF.eficial effects of SGLT2 inhibitors on HF.)
Cronshaw 2019 Photobiomodul Photomed Laser Surg + (Background: The clinical therapeutic benef … Background: The clinical therapeutic benefits of Photobiomodulation (PBM) therapy have been well established in many clinical scenarios. However, we are far from having developed a complete understanding of the underlying mechanisms of photon-biological tissue interactions. Concurrent to ongoing PBM studies, there are several parallel fields with evidences from cell and tissue physiology such as evolutionary biology, photobiology, and microbiology among others. Objective: This review is focused on extrapolating evidences from an expanded range of studies that may contribute to a better understanding of PBM mechanisms especially focusing on analgesia. Further, the choice of a PBM device source and relevant dosimetry with regards to specific mechanisms are discussed to enable broader clinical use of PBM therapies. Materials and methods: This discussion article is referenced from an expanded range of peer reviewed publications, including literature associated with evolutionary biology, microbiology, oncology, and photo-optical imaging technology, amongst others. Results and discussion: Materials drawn from many disparate disciplines is described. By inference from the current evidence base, a novel theory is offered to partially explain the cellular basis of PBM-induced analgesia. It is proposed that this may involve the activity of a class of transmembrane proteins known as uncoupling proteins. Furthermore, it is proposed that this may activate the heat stress protein response and that intracellur microthermal inclines may be of significance in PBM analgesia. It is suggested that the PBM dose response as a simple binary model of PBM effects as represented by the Arndt-Schulz law is clinically less useful than a multiphasic biological response. Finally, comments are made concerning the nature of photon to tissue interaction that can have significance in regard to the effective choice and delivery of dose to clinical target. Conclusions: It is suggested that a re-evaluation of phototransduction pathways may lead to an improvement in outcome in phototheraphy. An enhanced knowledge of safe parameters and a better knowledge of the mechanics of action at target level will permit more reliable and predictable clinical gain and assist the acceptance of PBM therapy within the wider medical community.herapy within the wider medical community.)
Ward 2015 Abstract IOC106 + (Background: The heart is a highly aerobic … Background: The heart is a highly aerobic organ with more than 90% of ATP regenerated by oxidative phosphorylation (OXPHOS) in the mitochondria. Mitochondrial dysfunction has been identified as a hallmark in the transition of compensatory hypertrophy to heart failure. However, the contribution of mitochondrial dysfunction to the contractile deficit is debated.Objectives: To determine if mitochondrial energy supply compromises contractile function in right ventricular (RV) hypertrophy.Methods: Rats were injected with monocrotaline (MCT) to induce pulmonary artery hypertension and RV hypertrophy, or saline (CON) for age-matched controls. Four weeks post-injection, multicellular cardiac trabeculae (length 2-3 mm, diameter 150-250 µm) were micro-dissected from the RV and mounted on an inverted microscope between a force transducer and a length changer. Steady-state force and intracellular Ca2+ transients were measured prior to saponin "skinning" of the sarcolemma to allow buffer access to the cytosol without damaging organelle membranes. Contraction and relaxation of the trabeculae was then assessed using buffered Ca2+ solutions, with and without exogenous ATP added to the superfusate.Results: MCT trabeculae produced similar force to CON despite having lower Ca2+ transients. Following skinning, CON trabeculae showed no change in the maximum Ca2+-activated force when exogenous ATP was removed from superfusate, while MCT trabeculae showed smaller contractures without exogenous ATP when stimulated with saturating Ca2+.Discussion: In this MCT model of compensated right ventricular hypertrophy there appears to be only a small contribution of mitochondrial dysfunction to contraction/relaxation when intracellular Ca2+ is controlled. This protocol can be used to further examine energy specific deficits in the failing heart, and to investigate the effects of drugs that modulate mitochondrial energy supply on contractile function. heart, and to investigate the effects of drugs that modulate mitochondrial energy supply on contractile function.)
Bociaga-Jasik 2013 Pharmacol Rep + (Background: The iatrogenic, HIV-related li … Background: The iatrogenic, HIV-related lipodystrophy is associated with development of the significant metabolic and cardiovascular complications. The underlying mechanisms of antiretroviral (ARV) drugs are not completely explored. Methods: The aim of the study was to characterize effects of the protease inhibitor (PI) - saquinavir (SQV) on metabolic functions, and gene expression during differentiation in cells (Chub-S7) culture. Results: SQV in concentrations observed during antiretroviral therapy (ART) significantly decreased mitochondrial membrane potential (MMP), oxygen consumption and ATP generation. The effects were greater in already differentiated cells. This was accompanied by characteristic changes in the expression of the genes involved in endoplasmic reticulum (ER) stress, and differentiation (lipid droplet formation) process such as: WNT10a, C/EBPa, AFT4, CIDEC, ADIPOQ, LPIN1. Conclusions: The results indicate that SQV affects not only metabolic (mitochondrial) activity of adipocytes, but affects the expression of genes related to differentiation and to a lesser extent to cell apoptosis. and to a lesser extent to cell apoptosis.)
Wohlwend 2013 Thesis + (Background: The mechanistically relation b … Background: The mechanistically relation between low oxygen metabolism and poor health remains unresolved.Methods: To pursue this aspect further, we measured mitochondrial oxidative phosphorylation (OXPHOS) capacity in permeabilized fibres of gastrocnemius (GASTRO) and left ventricle (LV) of the heart in 22 female rats artificially inbred for low- and high running capacity (LCR; HCR, respectively) for 30 generations. The rats were randomized to either sedate (LCRsed; HCRsed) or aerobic interval training (AIT) sessions 5 times a week for 1 month and then 2 times a week for 8 months (LCRext; HCRext).Results: There was a significant effect of training and inbreeding on maximal oxygen uptake in these rats. Baseline results for GASTRO in LCRsed compared to HCRsed showed reduced fat oxidation, CI-, CII linked respiration and maximal OXPHOS (CI- and CII linked respiration). Activity of the TCA cycle enzyme citrate synthase (CS) was lower in LCR compared to HCR. Mitochondrial content independent calculations indicated an enzyme defect in β-oxidation, and that mitochondrial coupling efficiency of electron transfer during β-oxidationwas impaired in LCRsed compared to HCRsed. AIT improved all these variables such that there was no difference in fat oxidation, CI-, CII linked respiration or maximal OXPHOS between LCRext and HCRext. These improvements were likely due to an increase in mitochondrial density, but also qualitative improvementsparticularly in fat oxidation (coupling efficiency and relative flux) were found.Baseline results for LV in LCRsed compared to HCRsed showed reduced CII linked respiration, maximal OXPHOS and similar activity of CS in LCRsed compared to HCRsed. Flux ratios as well as mitochondrial coupling efficiency during β-oxidation were similar between LCRsed and HCRsed. AIT improved maximalOXPHOS such that there was no difference between LCRext and HCRext. Interestingly, AIT had no effect on CS-activity in neither LCR nor HCR, suggesting primarily qualitative adjustments to exercise training in heart,mainly within β-oxidation and CII linked respiration. There was no dyscoupling effect as a result of phosphorylative constraint on electron transfer through complex I-IV by ATPsynthase in GASTRO or in LV, suggesting that ET-pathway rather than the phosphorylation system is limiting maximal ATP production in rats.Conclusions: Sedentary rats that contrast in intrinsic low- and high aerobic capacity differ significantly in OXHPOS, mitochondrial coupling efficiency and coupling control in GASTRO as well as in maximal OXPHOS in LV. Nine months of AIT was able to reverse all these initial impairments of mitochondrial function both in the heart and in the periphery, possibly through an interplay of different mechanisms. These findings might explain some of the poor health features of low capacity rats and suggest training-induced plasticity.s and suggest training-induced plasticity.)
Bilan 2014 Biochim Biophys Acta + (Background: The ratio of NAD(+)/NADH is a … Background: The ratio of NAD(+)/NADH is a key indicator that reflects the overall redox state of the cells. Until recently, there were no methods for real time NAD(+)/NADH monitoring in living cells. Genetically encoded fluorescent probes for NAD(+)/NADH are fundamentally new approach for studying the NAD(+)/NADH dynamics.Methods: We developed a genetically encoded probe for the nicotinamide adenine dinucleotide, NAD(H), redox state changes by inserting circularly permuted YFP into redox sensor T-REX from Thermus aquaticus. We characterized the sensor in vitro using spectrofluorometry and in cultured mammalian cells using confocal fluorescent microscopy.Results: The sensor, named RexYFP, reports changes in the NAD(+)/NADH ratio in different compartments of living cells. Using RexYFP, we were able to track changes in NAD(+)/NADH in cytoplasm and mitochondrial matrix of cells under a variety of conditions. The affinity of the probe enables comparison of NAD(+)/NADH in compartments with low (cytoplasm) and high (mitochondria) NADH concentration. We developed a method of eliminating pH-driven artifacts by normalizing the signal to the signal of the pH sensor with the same chromophore.Conclusion: RexYFP is suitable for detecting the NAD(H) redox state in different cellular compartments.General significance: RexYFP has several advantages over existing NAD(+)/NADH sensors such as smallest size and optimal affinity for different compartments. Our results show that normalizing the signal of the sensor to the pH changes is a good strategy for overcoming pH-induced artifacts in imaging.vercoming pH-induced artifacts in imaging.)
Lettieri-Barbato 2019 Mol Metab + (Background: Thermogenic adipocytes reorgan … Background: Thermogenic adipocytes reorganize their metabolism during cold exposure. Metabolic reprogramming requires readily available bioenergetics substrates, such as glucose and fatty acids, to increase mitochondrial respiration and produce heat via the uncoupling protein 1 (UCP1). This condition generates a finely-tuned production of mitochondrial reactive oxygen species (ROS) that support non-shivering thermogenesis.Scope of review: Herein, the findings underlining the mechanisms that regulate ROS production and control of the adaptive responses tuning thermogenesis in adipocytes are described. Furthermore, this review describes the metabolic responses to substrate availability and the consequence of mitochondrial failure to switch fuel oxidation in response to changes in nutrient availability. A framework to control mitochondrial ROS threshold to maximize non-shivering thermogenesis in adipocytes is provided.Major conclusions: Thermogenesis synchronizes fuel oxidation with an acute and transient increase of mitochondrial ROS that promotes the activation of redox-sensitive thermogenic signaling cascade and UCP1. However, an overload of substrate flux to mitochondria causes a massive and damaging mitochondrial ROS production that affects mitochondrial flexibility. Finding novel thermogenic redox targets and manipulating ROS concentration in adipocytes appears to be a promising avenue of research for improving thermogenesis and counteracting metabolic diseases.esis and counteracting metabolic diseases.)
Mikulas 2020 Materials + (Background: Triethylene glycol dimethacryl … Background: Triethylene glycol dimethacrylate (TEGDMA) monomers released from resin matrix are toxic to dental pulp cells, induce apoptosis, oxidative stress and decrease viability. Recently, mitochondrial complex I (CI) was identified as a potential target of TEGDMA. In isolated mitochondria supported by CI, substrates oxidation and ATP synthesis were inhibited, reactive oxygen species production was stimulated. Contrary to that, respiratory Complex II was not impaired by TEGDMA. The beneficial effects of electron carrier compound methylene blue (MB) are proven in many disease models where mitochondrial involvement has been detected. In the present study, the bioenergetic effects of MB on TEGDMA-treated isolated mitochondria and on human dental pulp stem cells (DPSC) were analyzed.Methods: Isolated mitochondria and DPSC were acutely exposed to low millimolar concentrations of TEGDMA and 2 μM concentration of MB. Mitochondrial and cellular respiration and glycolytic flux were measured by high resolution respirometry and by Seahorse XF extracellular analyzer. Mitochondrial membrane potential was measured fluorimetrically.Results: MB partially restored the mitochondrial oxidation, rescued membrane potential in isolated mitochondria and significantly increased the impaired cellular O2 consumption in the presence of TEGDMA.Conclusion: MB is able to protect against TEGDMA-induced CI damage, and might provide protective effects in resin monomer exposed cells.Copyright © 2018. Published by Elsevier Inc.pyright © 2018. Published by Elsevier Inc.)
Matsumoto 2021 Circ Heart Fail + (Background: We recently reported that trea … Background: We recently reported that treatment with rhBDNF (recombinant human brain-derived neurotrophic factor) improved the reduced exercise capacity of mice with heart failure (HF) after myocardial infarction (MI). Since BDNF is reported to enhance fatty acid oxidation, we herein conducted an in vivo investigation to determine whether the improvement in exercise capacity is due to the enhancement of the fatty acid oxidation of skeletal muscle via the AMPKα-PGC1α (adenosine monophosphate-activated protein kinase-ɑ-proliferator-activated receptor-r coactivator-1ɑ) axis.Methods: MI and sham operations were conducted in C57BL/6J mice. Two weeks postsurgery, we randomly divided the MI mice into groups treated with rhBDNF or vehicle for 2 weeks. AMPKα-PGC1α signaling and mitochondrial content in the skeletal muscle of the mice were evaluated by Western blotting and transmission electron microscopy. Fatty acid β-oxidation was examined by high-resolution respirometry using permeabilized muscle fiber. BDNF-knockout mice were treated with 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside, an activator of AMPK.Results: The rhBDNF treatment significantly increased the expressions of phosphorylated AMPKα and PGC1α protein and the intermyofibrillar mitochondrial density in the MI mice. The lowered skeletal muscle mitochondrial fatty acid oxidation was significantly improved in the rhBDNF-treated MI mice. The reduced exercise capacity and mitochondrial dysfunction of the BDNF-knockout mice were improved by 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside.Conclusions: Beneficial effects of BDNF on the exercise capacity of mice with HF are mediated through an enhancement of fatty acid oxidation via the activation of AMPKα-PGC1α in skeletal muscle. BDNF may become a therapeutic option to improve exercise capacity as an alternative or adjunct to exercise training.ternative or adjunct to exercise training.)
Zucker 2020 Biol Sex Differ + (Background: Women experience adverse drug … Background: Women experience adverse drug reactions, ADRs, nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood. Most drugs currently in use were approved based on clinical trials conducted on men, so women may be overmedicated. We determined whether sex differences in drug pharmacokinetics, PKs, predict sex differences in ADRs.Methods: Searches of the ISI Web of Science and PubMed databases were conducted with combinations of the terms: drugs, sex or gender, pharmacokinetics, pharmacodynamics, drug safety, drug dose, and adverse drug reaction, which yielded over 5000 articles with considerable overlap. We obtained information from each relevant article on significant sex differences in PK measures, predominantly area under the curve, peak/maximum concentrations, and clearance/elimination rates. ADRs were identified from every relevant article and recorded categorically as female-biased, male-biased, or not sex-biased.Results: For most of the FDA-approved drugs examined, elevated blood concentrations and longer elimination times were manifested by women, and these PKs were strongly linked to sex differences in ADRs. Of the 86 drugs evaluated, 76 had higher PK values in women; for 59 drugs with clinically identifiable ADRs, sex-biased PKs predicted the direction of sex-biased ADRs in 88 % of cases. Ninety-six percent of drugs with female-biased PK values were associated with a higher incidence of ADRs in women than men, but only 29 % of male-biased PKs predicted male-biased ADRs. Accessible PK information is available for only a small fraction of all drugs.Conclusions: Sex differences in pharmacokinetics strongly predict sex-specific ADRs for women but not men. This sex difference was not explained by sex differences in body weight. The absence of sex-stratified PK information in public records for hundreds of drugs raises the concern that sex differences in PK values are widespread and of clinical significance. The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions. We recommend evidence-based dose reductions for women to counteract this sex bias.ons for women to counteract this sex bias.)
Forte 2019 Biochim Biophys Acta Bioenerg + (Bacteria can not only encounter carbon mon … Bacteria can not only encounter carbon monoxide (CO) in their habitats but also produce the gas endogenously. Bacterial respiratory oxidases, thus, represent possible targets for CO. Accordingly, host macrophages were proposed to produce CO and release it into the surrounding microenvironment to sense viable bacteria through a mechanism that in ''Escherichia'' (''E.'') ''coli'' was suggested to involve the targeting of a bd-type respiratory oxidase by CO. The aerobic respiratory chain of ''E. coli'' possesses three terminal quinol:O2-oxidoreductases: the heme-copper oxidase bo3 and two copper-lacking bd-type oxidases, bd-I and bd-II. Heme-copper and bd-type oxidases differ in the mechanism and efficiency of proton motive force generation and in resistance to oxidative and nitrosative stress, cyanide and hydrogen sulfide. Here, we investigated at varied O2 concentrations the effect of CO gas on the O2 reductase activity of the purified cytochromes bo3, bd-I and bd-II of ''E. coli''. We found that CO, in competition with O2, reversibly inhibits the three enzymes. The inhibition constants Ki for the bo3, bd-I and bd-II oxidases are 2.4 ± 0.3, 0.04 ± 0.01 and 0.2 ± 0.1 μM CO, respectively. Thus, in ''E. coli'', bd-type oxidases are more sensitive to CO inhibition than the heme-copper cytochrome bo3. The possible physiological consequences of this finding are discussed.Copyright © 2019 Elsevier B.V. All rights reserved.The possible physiological consequences of this finding are discussed. Copyright © 2019 Elsevier B.V. All rights reserved.)
Luef 2015 Nat Commun + (Bacteria from phyla lacking cultivated rep … Bacteria from phyla lacking cultivated representatives are widespread in natural systems and some have very small genomes. Here we test the hypothesis that these cells are small and thus might be enriched by filtration for coupled genomic and ultrastructural characterization. Metagenomic analysis of groundwater that passed through a ~0.2-μm filter reveals a wide diversity of bacteria from the WWE3, OP11 and OD1 candidate phyla. Cryogenic transmission electron microscopy demonstrates that, despite morphological variation, cells consistently have small cell size (0.009±0.002 μm3). Ultrastructural features potentially related to cell and genome size minimization include tightly packed spirals inferred to be DNA, few densely packed ribosomes and a variety of pili-like structures that might enable inter-organism interactions that compensate for biosynthetic capacities inferred to be missing from genomic data. The results suggest that extremely small cell size is associated with these relatively common, yet little known organisms.h these relatively common, yet little known organisms.)
Kaila 2021 Nat Rev Microbiol + (Bacteria power their energy metabolism usi … Bacteria power their energy metabolism using membrane-bound respiratory enzymes that capture chemical energy and transduce it by pumping protons or Na+ ions across their cell membranes. Recent breakthroughs in molecular bioenergetics have elucidated the architecture and function of many bacterial respiratory enzymes, although key mechanistic principles remain debated. In this Review, we present an overview of the structure, function and bioenergetic principles of modular bacterial respiratory chains and discuss their differences from the eukaryotic counterparts. We also discuss bacterial supercomplexes, which provide central energy transduction systems in several bacteria, including important pathogens, and which could open up possible avenues for treatment of disease.possible avenues for treatment of disease.)
MiPNet28.08 Oroboros O2k Series J manual + (Baglivo E, Grings M, Gnaiger E (2023) Mitochondr Physiol Network 28.08(02)1-22.)
Scott 2009 Am J Physiol Regul Integr Comp Physiol + (Bar-headed geese fly at altitudes of up to … Bar-headed geese fly at altitudes of up to 9,000 m on their biannual migration over the Himalayas. To determine whether the flight muscle of this species has evolved to facilitate exercise at high altitude, we compared the respiratory properties of permeabilized muscle fibers from bar-headed geese and several low-altitude waterfowl species. Respiratory capacities were assessed for maximal ADP stimulation (with single or multiple inputs to the electron transport system) and cytochrome oxidase excess capacity (with an exogenous electron donor) and were generally 20–40% higher in bar-headed geese when creatine was present. When respiration rates were extrapolated to the entire pectoral muscle mass, bar-headed geese had a higher mass-specific aerobic capacity. This may represent a surplus capacity that counteracts the depressive effects of hypoxia on mitochondrial respiration. However, there were no differences in activity for mitochondrial or glycolytic enzymes measured in homogenized muscle. The [ADP] leading to half-maximal stimulation (''K''m) was approximately twofold higher in bar-headed geese (10 vs. 4–6 µM), and, while creatine reduced ''K''m by 30% in this species, it had no effect on ''K''m in low-altitude birds. Mitochondrial creatine kinase may therefore contribute to the regulation of oxidative phosphorylation in flight muscle of bar-headed geese, which could promote efficient coupling of ATP supply and demand. However, this was not based on differences in creatine kinase activity in isolated mitochondria or homogenized muscle. The unique differences in bar-headed geese existed without prior exercise or hypoxia exposure and were not a result of phylogenetic history, and may, therefore, be important evolutionary specializations for high-altitude flight.therefore, be important evolutionary specializations for high-altitude flight.)
Scott 2009 Proc Biol Sci + (Bar-headed geese migrate over the Himalaya … Bar-headed geese migrate over the Himalayas at up to 9000 m elevation, but it is unclear how they sustain the high metabolic rates needed for flight in the severe hypoxia at these altitudes. To better understand the basis for this physiological feat, we compared the flight muscle phenotype of bar-headed geese with that of low altitude birds (barnacle geese, pink-footed geese, greylag geese and mallard ducks). Bar-headed goose muscle had a higher proportion of oxidative fibres. This increased muscle aerobic capacity, because the mitochondrial volume densities of each fibre type were similar between species. However, bar-headed geese had more capillaries per muscle fibre than expected from this increase in aerobic capacity, as well as higher capillary densities and more homogeneous capillary spacing. Their mitochondria were also redistributed towards the subsarcolemma (cell membrane) and adjacent to capillaries. These alterations should improve O2 diffusion capacity from the blood and reduce intracellular O2 diffusion distances, respectively. The unique differences in bar-headed geese were much greater than the minor variation between low altitude species and existed without prior exercise or hypoxia exposure, and the correlation of these traits to flight altitude was independent of phylogeny. In contrast, isolated mitochondria had similar respiratory capacities, O2 kinetics and phosphorylation efficiencies across species. Bar-headed geese have therefore evolved for exercise in hypoxia by enhancing the O2 supply to flight muscle.or exercise in hypoxia by enhancing the O2 supply to flight muscle.)
Douros 2019 JCI Insight + (Bariatric surgeries including vertical sle … Bariatric surgeries including vertical sleeve gastrectomy (VSG) ameliorate obesity and diabetes. Weight-loss and accompanying increases to insulin sensitivity contribute to improved glycemia after surgery, however, studies in humans also suggest weight-independent actions of bariatric procedures to lower blood glucose, possibly by improving insulin secretion. To evaluate this hypothesis, we compared VSG operated mice with pair-fed, sham-surgical controls (PF-Sham) 2 weeks after surgery. This paradigm yielded similar post-operative body weight and insulin sensitivity between VSG and calorically restricted PF-Sham animals. However, VSG improved glucose tolerance and markedly enhanced insulin secretion during oral nutrient and intraperitoneal glucose challenges compared to controls. Islets from VSG mice displayed a unique transcriptional signature enriched for genes involved in Ca2+ signaling and insulin secretion pathways. This finding suggests that bariatric surgery leads to intrinsic changes within the islet that alter function. Indeed, islets isolated from VSG mice had increased glucose-stimulated insulin secretion and a left-shifted glucose sensitivity curve compared to islets from PF-Sham mice. Isolated islets from VSG animals showed corresponding increases in the pulse duration of glucose-stimulated Ca2+ oscillations. Together these findings demonstrate a weight-independent improvement in glycemic control following VSG, which is, in part, driven by improved insulin secretion and associated with substantial changes in islet gene expression. These results support a model in which β-cells play a key role in the adaptation to bariatric surgery and the improved glucose tolerance that is typical of these procedures.he improved glucose tolerance that is typical of these procedures.)
West 1999 J Appl Physiol + (Barometric pressures (PB) near the summit … Barometric pressures (PB) near the summit of Mt. Everest (altitude 8, 848 m) are of great physiological interest because the partial pressure of oxygen is very near the limit for human survival. Until recently, the only direct measurement on the summit was 253 Torr, which was obtained in October 1981, but, despite being only one data point, this value has been used by several investigators. Recently, two new studies were carried out. In May 1997, another direct measurement on the summit was within approximately 1 Torr of 253 Torr, and meteorologic data recorded at the same time from weather balloons also agreed closely. In the summer of 1998, over 2,000 measurements were transmitted from a barometer placed on the South Col (altitude 7,986 m). The mean PB values during May, June, July, and August were 284, 285, 286, and 287 Torr, respectively, and there was close agreement with the PB-altitude (h) relationship determined from the 1981 data. The PB values are well predicted from the equation PB = exp (6.63268 - 0.1112 h - 0.00149 h2), where h is in kilometers. The conclusion is that on days when the mountain is usually climbed, during May and October, the summit pressure is 251-253 Torr.ober, the summit pressure is 251-253 Torr.)
Chicco 2016c Abstract MitoFit Science Camp 2016 + (Barth Syndrome (3-methylglutaconic aciduri … Barth Syndrome (3-methylglutaconic aciduria type II; BTHS) is a childhood onset cardioskeletal myopathy that results from mutations in the tafazzin gene encoding a phospholipid transacylase responsible for remodeling cardiolipin in the inner mitochondrial membrane. Cardiolipin is known to be required for optimal function and assembly of respiratory supercomplexes in the inner membrane, but precisely how loss of tafazzin function impairs mitochondrial respiratory function leading to BTHS is unclear. We utilized high-resolution respirometry (HHR) with a variety of substrate combinations to investigate the sites of cardiac mitochondrial dysfunction in the tafazzin shRNA (Taz) mouse model of BTHS, which exhibits ~90% tafazzin deficiency and cardiolipin abnormalities characteristic of BTHS in humans. Initial HRR studies revealed 50% lower rates of Complex I (CI)-linked OXPHOS respiration in Taz mitochondria compared to wild-type (WT) controls using pyruvate & malate as substrates, while succinate (CII)-supported OXPHOS and maximal enzymatic capacities of complexes I, II-IV and IV were only suppressed by 12-20%. Surprisingly, CI-linked OXPHOS supported by glutamate & malate was 50% higher in Taz, approximating rates of maximal pyruvate-supported OXPHOS in WT, arguing against CI as a primary site of OXPHOS limitation in Taz. To investigate fatty acid-supported OXPHOS, long- (16:0; palmitate) and medium-chain (8:0; octanoate) fatty acids were supplied bound to carnitine (CPT1-independent) or CoA (CPT1-dependent) to address effects on mitochondrial fatty acid transport, activation and acyl-CoA dehydrogenase isozyme-specific function [1]. Results demonstrated significant impairment of respiration supported by both medium and long-chain acyl-carnitines in Taz compared to WT mitochondria, which was blunted when palmitoyl-CoA & carnitine were used as substrates. Interestingly, metabolomic analysis of cardiac tissues revealed an 41% decrease in pantothenic acid that corresponded to a similar loss of mitochondrial CoA content in Taz compared to WT hearts. To test the hypothesis that CoA deficiency limits pyruvate and fatty acid oxidation in Taz, mitochondria were pre-incubated with 100 μM CoA to restore levels prior to repeating HRR experiments with pyruvate or palmitoylcarnitine (& malate). This increased CoA content in both Taz and WT mitochondria and partially rescued OXPHOS supported by substrates to near WT levels, despite having no significant effect on OXPHOS rates with either substrate in WT.ficant effect on OXPHOS rates with either substrate in WT.)
Johnson 2018 J Mol Cell Cardiol + (Barth Syndrome (BTHS) is an X-linked reces … Barth Syndrome (BTHS) is an X-linked recessive disorder characterized by cardiomyopathy and muscle weakness. The underlying cause of BTHS is a mutation in the tafazzin (TAZ) gene, a key enzyme of cardiolipin biosynthesis. The lack of CL arising from loss of TAZ function results in destabilization of the electron transport system, promoting oxidative stress that is thought to contribute to development of cardioskeletal myopathy. Indeed, ''in vitro'' studies demonstrate that mitochondria-targeted antioxidants improve contractile capacity in TAZ-deficient cardiomyocytes. The purpose of the present study was to determine if resolving mitochondrial oxidative stress would be sufficient to prevent cardiomyopathy and skeletal myopathy ''in vivo'' using a mouse model of BTHS. To this end we crossed mice that overexpress catalase in the mitochondria (MCAT mice) with TAZ-deficient mice (TAZKD) to produce TAZKD mice that selectively overexpress catalase in the mitochondria (TAZKD+MCAT mice). TAZKD+MCAT mice exhibited decreased mitochondrial H2O2 emission and lipid peroxidation compared to TAZKD littermates, indicating decreased oxidative stress. Despite the improvements in oxidative stress, TAZKD+MCAT mice developed cardiomyopathy and mild muscle weakness similar to TAZKD littermates. These findings indicate that resolving oxidative stress is not sufficient to suppress cardioskeletal myopathy associated with BTHS.fficient to suppress cardioskeletal myopathy associated with BTHS.)
Kutschka 2023 Basic Res Cardiol + (Barth Syndrome (BTHS) is an inherited card … Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation. acids to sustain energy production and antioxidation.)
Claiborne 2013 Thesis + (Barth Syndrome is a mitochondrial disease … Barth Syndrome is a mitochondrial disease associated with exercise intolerance andcardioskeletal myopathy resulting from mutations in the tafazzin (taz) gene. The present studycharacterized skeletal muscle mitochondrial function and exercise capacity of a taz shRNAmouse model of Barth Syndrome (90% taz-deficient), and examined the effect of exercisetraining on these parameters. Mitochondrial respiratory function was assessed, in mitochondriafreshly isolated from hindlimb muscles, using an Oroboros O2K respirometer with pyruvate +malate as substrates, oligomycin as an ATP synthase inhibitor, and carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) to establish maximal activity. A pre-training GXTrevealed profound exercise intolerance, which corresponded to reduced respiratory capacity,citrate synthase (CS) and ETC complex 1 protein content of muscle mitochondria in the taz vs.age-matched wild-type (WT) mice. Based on the pre-training GXT, exercise training wasconducted at 12-17 m/min, 0% grade for 60 min/d, 5d/wk, for 4 wks. Exercise training elicited a99% increase in GXT run time in the taz mice ''P'' < 0.01 vs. pre-training), but failed to increasetimes to those of sedentary WT mice. Training significantly decreased state 3 respiratorycapacity of muscle mitochondria from exercised mice (wild type sedentary (WTS): 4992.59 ±371.35, wild type exercised (WTX): 3779.60 ± 561.43, taz sedentary (TazS): 2978.50 ± 383.53,TazS: 1827.55 ± 525.17 (pmolO2/(s*mg), ''P'' = 0.02, Sed. vs. Ex.), and significantly decreasedmitochondrial CS activity in taz mice (WTS: 4.48 ± 0.51, WTX: 3.87 ± 0.69, TazS: 3.21 ± 0.54,taz exercised (TazX): 1.63 ± 0.69 (relative absorbance/gram of protein) (RU/g), ''P'' = 0.01).Training also tended to reduce mitochondrial lactate dehydrogenase (LDH) and monocarboxylatetransporter 1 (MCT1) activities, MnSOD content, and 4-hydroxnonenal-protein adducts (index ofoxidative stress), but tended to increase mitochondrial UCP3 in exercised WT and taz mice.Interestingly, training significantly increased muscle levels of CS (WTS: 1.491 ± 0.112, WTX:1.792 ± 0.143, TazS: 1.325 ± 0.108, TazX: 1.550 ± 0.143 (RU/g),'' P'' = 0.05 Sed. v. Ex.),suggesting increased muscle mitochondrial content with training. This study indicates thatexercise training improves functional capacity of taz deficient mice and induces selectivemitochondrial protein remodeling during mitochondrial biogenesis that perhaps mitigatesoxidative stress while adapting to increased metabolic demand.while adapting to increased metabolic demand.)
Chicco 2013 Abstract MiP2013 Poster + (Barth Syndrome is a mitochondrial disease … Barth Syndrome is a mitochondrial disease associated with exercise intolerance and cardioskeletal myopathy resulting from mutations in the tafazzin (taz) gene. Taz encodes a phospholipid transacylase believed to be important for the remodeling of cardiolipin and maintaining optimal mitochondrial membrane function. The present study characterized skeletal muscle mitochondrial function and exercise capacity of a new taz shRNA mouse model of Barth Syndrome (90% taz-deficient), and examined the effect of exercise training on these parameters. Mitochondrial respiratory function was assessed in mitochondria freshly isolated from hindlimb muscles using an Oroboros Oxygraph-2k with pyruvate+malate as substrates. A pre-training treadmill graded exercise test (GXT) revealed profound exercise intolerance in taz mice, which corresponded to reduced respiratory capacity, citrate synthase (CS) and ET-pathway Complex I protein content of muscle mitochondria in the taz vs. age-matched wild-type (WT) mice. Based on the pre-training GXT, exercise training was conducted at 12-17 m/min, 0% grade for 60 min/d, 5 d/wk. Exercise training elicited a 99% increase in GXT run time in the taz mice (P<0.01 vs. pre-training), but failed to increase levels to that of sedentary WT mice. Unexpectedly, training significantly decreased OXPHOS capacity of isolated muscle mitochondria from exercised mice (WTS: 4993 ± 371, WTX: 3780 ± 561, TazS: 2979 ± 384, TazS: 1828 ± 525 (pmol/(s*mg), P=0.02 Sed. vs. Ex.), and significantly decreased mitochondrial CS activity in taz mice (WTS: 4.48 ± 0.51, WTX: 3.87 ± 0.69, TazS: 3.21 ± 0.54, TazX: 1.63 ± 0.69 (RU/g), P=0.01). Training tended to reduce mitochondrial lactate dehydrogenase (LDH) and monocarboxylate transporter 1 (MCT1) activities, MnSOD content, and 4-hydroxnonenal-protein adducts (index of oxidative stress), but tended to increase mitochondrial UCP3 in exercised WT and taz mice. Interestingly, training significantly increased CS activity in total muscle homogenates (WTS: 1.491 ± 0.112, WTX: 1.792 ± 0.143, TazS: 1.325 ± 0.108, TazX: 1.550 ± 0.143 (RU/g), P=0.05 Sed. v. Ex.), suggesting a training-induced increase in whole-muscle oxidative capacity despite a lower OXPHOS capacity per mg protein of isolated mitochondria. This study indicates that exercise training improves functional capacity of taz deficient mice despite persistent mitochondrial respiratory dysfunction, and induces selective remodeling of mitochondria in skeletal muscle perhaps to mitigate oxidant production from a dysfunctional respiratory system while adapting to increased metabolic demand.while adapting to increased metabolic demand.)
Le 2020 J Biol Chem + (Barth syndrome (BTHS) is a mitochondrial m … Barth syndrome (BTHS) is a mitochondrial myopathy resulting from mutations in the tafazzin (TAZ) gene encoding a phospholipid transacylase required for cardiolipin remodeling. Cardiolipin is phospholipid of the inner mitochondrial membrane essential for the function of numerous mitochondrial proteins and processes. However, it is unclear how tafazzin deficiency impacts cardiac mitochondrial metabolism. To address this question while avoiding confounding effects of cardiomyopathy on mitochondrial phenotype, we utilized Taz-shRNA "knockdown" (TazKD) mice, which exhibit defective cardiolipin remodeling and respiratory supercomplex instability characteristic of human BTHS, but normal cardiac function into adulthood. Consistent with previous reports from other models, mitochondrial H2O2 emission and oxidative damage were greater in TazKD than in wild-type (WT) hearts, but there were no differences in oxidative phosphorylation coupling efficiency or membrane potential. Fatty acid and pyruvate oxidation capacities were 40-60% lower in TazKD mitochondria, but an upregulation of glutamate oxidation supported respiration rates approximating those with pyruvate and palmitoylcarnitine in WT. Deficiencies in mitochondrial CoA and shifts in the cardiac acyl-CoA profile paralleled changes in fatty acid oxidation enzymes and acyl-CoA thioesterases suggesting limitations of CoA availability or "trapping" in TazKD mitochondrial metabolism. Incubation of TazKD mitochondria with exogenous CoA partially rescued pyruvate and palmitoylcarnitine oxidation capacities, implicating dysregulation of CoA-dependent intermediary metabolism rather than respiratory chain defects in the bioenergetic impacts of tafazzin-deficiency. These findings support links among cardiolipin abnormalities, respiratory supercomplex instability and mitochondrial oxidant production, and shed new light on the distinct metabolic consequences of tafazzin-deficiency in the mammalian heart.l oxidant production, and shed new light on the distinct metabolic consequences of tafazzin-deficiency in the mammalian heart.)
Kiebish 2013 J Lipid Res + (Barth syndrome is a complex metabolic diso … Barth syndrome is a complex metabolic disorder caused by mutations in the mitochondrial transacylase Tafazzin. Recently, an inducible Tafazzin shRNA knockdown mouse model was generated to deconvolute the complex bioenergetic phenotype of this disease. To investigate the underlying cause of hemodynamic dysfunction in Barth syndrome, we interrogated the cardiac structural and signaling lipidome of this mouse model as well as its myocardial bioenergetic phenotype. A decrease in the distribution of cardiolipin molecular species and robust increases in monolysocardiolipin and dilysocardiolipin were demonstrated. Additionally, the contents of choline and ethanolamine glycerophospholipid molecular species containing precursors for lipid signaling at the sn-2 position were altered. Lipidomic analyses revealed specific dysregulation of HETEs, prostanoids, as well as oxidized linoleic and docosahexaenoic metabolites. Bioenergetic interrogation uncovered differential substrate utilization as well as deceases in Complex III and CV activities. Transgenic expression of cardiolipin synthase or iPLA2γ ablation in Tafazzin deficient mice did not rescue the observed phenotype. These results underscore the complex nature of alterations in cardiolipin metabolism mediated by Tafazzin loss of function. Collectively, we identified specific lipidomic, bioenergetic and signaling alterations in a murine model that parallel those of Barth syndrome thereby providing novel insights into the pathophysiology of this debilitating disease.hophysiology of this debilitating disease.)
Chicco 2013 Abstract IOC79 + (Barth syndrome is an X-linked cardioskelet … Barth syndrome is an X-linked cardioskeletal myopathy that results from mutations in the Tafazzin (Taz) gene encoding a phospholipid transacylase required for the remodeling of the cardiolipin. Cardiolipin is an inner mitochondrial membrane phospholipid essential for the function of several mitochondrial proteins, but how Taz deficiency and defective cardiolipin remodeling influences mammalian mitochondrial function is unclear. We recently characterized the cardiac mitochondrial phenotype of a new Taz shRNA mouse model of BTHS by high resolution respirometry (HRR) on isolated mitochondria and permeabilized heart fibers, complemented by cardiac metabolomics and mitochondrial proteomic profiling. HRR revealed 40-60% lower rates of oxidative phosphorylation in Taz shRNA compared to wild-type (WT) mitochondria using pyruvate and palmitoylcarnitine (+ malate) as substrates in isolated subsarcolemmal and interfibrillar mitochondria, as well as permeabilized cardiac muscle fibers. Less robust impairments were seen in complex II-supported respiration (12%) and maximal enzymatic activity of respiratory complexes 1 (17%) and 4 (26%) in Taz shRNA vs. WT mitochondria. Unexpectedly, glutamate + malate respiration was markedly elevated in Taz shRNA vs. WT, reaching respiratory rates equal to those obtained with pyruvate and fatty acid substrates in WT mitochondria and fibers. Analysis of the Taz shRNA mitochondrial proteome revealed deficiencies in enzymes involved in amino acid catabolism, respiratory complex 1 assembly and fatty acid oxidation, while stress response enzymes, acyl-CoA thioesterases, and malate dehydrogenase were elevated. Cardiac metabolomics revealed a marked deficiency in pantothenic acid that paralleled 43% lower levels of CoA in Taz shRNA vs. WT mitochondria. To further investigate the potential role of CoA deficiency on the observed respiratory phenotype, isolated mitochondria were incubated with exogenous CoA prior to respirometry experiments, which significantly improved OXPHOS rates using pyruvate as a substrate. Taken together, our studies indicate that while Taz deficiency elicits expected impairments in respiratory chain function, the primary defect is a selective impairment of carbohydrate and lipid oxidation, perhaps due to a deficiency in mitochondria CoA that deserves further investigation.a CoA that deserves further investigation.)
Schulte 2013 Abstract MiP2013 + (Based on its presumed role in altering who … Based on its presumed role in altering whole-animal metabolic rate, the mitochondrion has become the focus of hypotheses that address the process of thermal adaptation. It has been proposed that temperature-induced limitations on mitochondrial function (due to passive thermal effects on biochemical activity or an imbalance between O2 supply and demand at low temperatures) affect whole organism performance and, as a result, cold-adapted or –acclimated species compensate with increased mitochondrial density and/or activity [1]. To address this hypothesis we use Fundulus heteroclitus, a teleost species with genetically distinct, locally adapted subpopulations (Northern, Southern, and Hybrid) which reside over a large thermal gradient. During acute high temperature shifts (37 °C), liver mitochondria isolated from 5 °C acclimated Northern Fundulus heteroclitus lose the capacity to perform oxidative phosphorylation. This phenomenon is not observed with fish acclimated to 15 and 25 °C, which is indicative of a cost of acclimation to low temperatures [2].To investigate the functional differences in mitochondrial properties as a result of low temperature acclimation we have acclimated Northern and Southern Fundulus heteroclitus to 5, 15 and 33 °C. We compare the kinetics of liver mitochondrial ADP-phosphorylation, proton conductance, and substrate oxidation during acute shifts to 5, 15, and 33 °C. In addition, we compare the rates of basal and maximum reactive oxygen species (ROS) production to assess its contribution as a result of proton conductance. Our current results indicate that during acute shifts to high temperature, cold-acclimated Northern killifish exhibit equivalent levels of LEAK respiration (i.e., proton leak) as room- and warm-temperature acclimated killifish while maintaining a lower membrane potential. This equivalent level of proton leak is reflected in no difference in ROS production when compared to the 15 °C acclimation. In addition, warm-acclimation appears to result in increased basal ROS production, while lowering maximal ROS. These results indicate that there are changes in mitochondrial function associated with low-temperature acclimation.sociated with low-temperature acclimation.)
Mkrtchyan 2018 Biochim Biophys Acta + (Based on the fact that traumatic brain inj … Based on the fact that traumatic brain injury is associated with mitochondrial dysfunction we aimed at localization of mitochondrial defect and attempted to correct it by thiamine.Interventional controlled experimental animal study was used. Adult male Sprague-Dawley rats were subjected to lateral fluid percussion traumatic brain injury. Thiamine was administered 1 h prior to trauma; cortex was extracted for analysis 4 h and 3 d after trauma.Increased expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor receptor 1 (TNF-R1) by 4 h was accompanied by a decrease in mitochondrial respiration with glutamate but neither with pyruvate nor succinate. Assays of TCA cycle flux-limiting 2-oxoglutarate dehydrogenase complex (OGDHC) and functionally linked enzymes (glutamate dehydrogenase, glutamine synthetase, pyruvate dehydrogenase, malate dehydrogenase and malic enzyme) indicated that only OGDHC activity was decreased. Application of the OGDHC coenzyme precursor thiamine rescued the activity of OGDHC and restored mitochondrial respiration. These effects were not mediated by changes in the expression of the OGDHC sub-units (E1k and E3), suggesting post-translational mechanism of thiamine effects. By the third day after TBI, thiamine treatment also decreased expression of TNF-R1. Specific markers of unfolded protein response did not change in response to thiamine.Our data point to OGDHC as a major site of damage in mitochondria upon traumatic brain injury, which is associated with neuroinflammation and can be corrected by thiamine. Further studies are required to evaluate the pathological impact of these findings in clinical settings.Copyright © 2018. Published by Elsevier B.V.pyright © 2018. Published by Elsevier B.V.)
Schniertshauer 2023 Curr Issues Mol Biol + (Based on the knowledge that many diseases … Based on the knowledge that many diseases are caused by defects in the metabolism of the cells and, in particular, in defects of the mitochondria, mitochondrial medicine starts precisely at this point. This new form of therapy is used in numerous fields of human medicine and has become a central focus within the field of medicine in recent years. With this form of therapy, the disturbed cellular energy metabolism and an out-of-balance antioxidant system of the patient are to be influenced to a greater extent. The most important tool here is mitotropic substances, with the help of which attempts are made to compensate for existing dysfunction. In this article, both mitotropic substances and accompanying studies showing their efficacy are summarized. It appears that the action of many mitotropic substances is based on two important properties. First, on the property of acting antioxidantly, both directly as antioxidants and via activation of downstream enzymes and signaling pathways of the antioxidant system, and second, via enhanced transport of electrons and protons in the mitochondrial respiratory chain.ns in the mitochondrial respiratory chain.)
Pfeiffer 2017 Free Radic Biol Med + (Bcl-xL is an anti-a … Bcl-xL is an anti-apoptotic protein that localizes to the outer mitochondrial membrane and influences mitochondrial bioenergetics by controlling Ca2+ influx into mitochondria. Here, we analyzed the effect of mitochondrial Bcl-xL on mitochondrial shape and function in knockout (KO), wild type and rescued mouse embryonic fibroblast cell lines. Mitochondria of KO cells were more fragmented, exhibited a reduced ATP concentration, and reduced oxidative phosphorylation (OXPHOS) suggesting an increased importance of ATP generation by other means. Under steady-state conditions, acidification of the growth medium as a readout for glycolysis was similar, but upon inhibition of ATP synthase with oligomycin, KO cells displayed an instant increase in glycolysis. In addition, forced energy production through OXPHOS by replacing glucose with galactose in the growth medium rendered KO cells more susceptible to mitochondrial toxins. KO cells had increased cellular reactive oxygen species and were more susceptible to oxidative stress, but had higher glutathione levels, which were however more rapidly consumed under conditions of oxidative stress. This coincided with an increased activity and protein abundance of the pentose phosphate pathway protein glucose-6-phosphate dehydrogenase, which generates NADPH necessary to regenerate reduced glutathione. KO cells were also less susceptible to pharmacological inhibition of the pentose phosphate pathway. We conclude that mitochondrial Bcl-xL is involved in maintaining mitochondrial respiratory capacity. Its deficiency causes oxidative stress, which is associated with an increased glycolytic capacity and balanced by an increased activity of the pentose phosphate pathway.alanced by an increased activity of the pentose phosphate pathway.)
Beatson Conference 2018 Glasgow UK + (Beatson International Cancer Conference, Glasgow, United Kingdom, 2018)
Chaix 2014 Cell Metab + (Because current therapeutics for obesity a … Because current therapeutics for obesity are limited and only offer modest improvements, novel interventions are needed. Preventing obesity with time-restricted feeding (TRF; 8–9 hr food access in the active phase) is promising, yet its therapeutic applicability against preexisting obesity, diverse dietary conditions, and less stringent eating patterns is unknown. Here we tested TRF in mice under diverse nutritional challenges. We show that TRF attenuated metabolic diseases arising from a variety of obesogenic diets, and that benefits were proportional to the fasting duration. Furthermore, protective effects were maintained even when TRF was temporarily interrupted by ad libitum access to food during weekends, a regimen particularly relevant to human lifestyle. Finally, TRF stabilized and reversed the progression of metabolic diseases in mice with preexisting obesity and type II diabetes. We establish clinically relevant parameters of TRF for preventing and treating obesity and metabolic disorders, including type II diabetes, hepatic steatosis, and hypercholesterolemia.patic steatosis, and hypercholesterolemia.)
Nunez-Figueredo 2014 Brain Res Bull + (Because mitochondrial oxidative stress and … Because mitochondrial oxidative stress and impairment are important mediators of neuronal damage in neurodegenerative diseases and in brain ischemia/reperfusion, in the present study, we evaluated theantioxidant and mitoprotective effect of a new promising neuroprotective molecule, JM-20, in mitochondriaand synaptosomes isolated from rat brains. JM-20 inhibited succinate-mediated H2O2 generation in both mitochondria and synaptosomes incubated in depolarized (high K+) medium at extremely low micromolar concentration and with identical IC50 values of 0.91 μM. JM-20 also repressed glucoseinducedH2O2 generation stimulated by rotenone or by antimycin A in synaptosomes incubated in high sodium-polarized medium at extremely low IC50 values of 0.395 μM and 2.452 μM, respectively. JM-20 was unable to react directly with H2O2 or with superoxide anion radicals but displayed a cathodic reductionpeak at −0.71 V, which is close to that of oxygen (−0.8 V), indicating high electron affinity. JM-20 also inhibited uncoupled respiration in mitochondria or synaptosomes and was a more effective inhibitor in the presence of the respiratory substrates glutamate/malate than in the presence of succinate. JM-20 also prevented Ca2+ -induced mitochondrial permeability transition pore opening, membrane potential dissipation and cytochrome ''c'' release, which are key pathogenic events during stroke. This molecule also prevented Ca2+ influx into synaptosomes and mitochondria; the former effect was a consequence of the latter because JM-20 inhibition followed the patterns of carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP), which is a classic mitochondrial uncoupler. Because the mitochondrion is considered an important source and target of neuronal cell death signaling after an ischemic insult, the antioxidant and protective effects of JM-20 against the deleterious effects of Ca2+ observed at the mitochondrial level in this study may endow this molecule with the ability to succeed in mitochondrion-targeted strategiesto combat ischemic brain damage.2+ observed at the mitochondrial level in this study may endow this molecule with the ability to succeed in mitochondrion-targeted strategies to combat ischemic brain damage.)
Ulgherait 2020 Nat Commun + (Because old age is associated with defects … Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male ''Drosophila'' significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, upregulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents overproliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in ''Drosophila'' and suggest a new potential anti-aging therapeutic target.w potential anti-aging therapeutic target.)
Larsen 2018 Physiol Rep + (Bed rest leads to impaired glucose toleran … Bed rest leads to impaired glucose tolerance. Whether this is linked to maladaptation's in skeletal muscle mitochondrial function and in particular to the level of reactive oxygen species (ROS) is at present unknown. The aim of this longitudinal study was to quantify skeletal muscle mitochondrial function (respiratory capacity and ROS production) together with glucose tolerance after 4 days of strict bed rest in healthy young male subjects (n = 14). Mitochondrial function was determined in permeabilized muscle fibers using high-resolution respirometry and fluorometry, mitochondrial content (citrate synthase [CS] activity) and antioxidant protein expression levels were assessed in parallel to this. Glucose tolerance was determined by means of oral glucose tolerance tests. Intrinsic mitochondrial respiratory capacity was augmented after the bed rest period (CI + IIP : 0.43 ± 0.12 vs. 0.55 ± 0.14 [pmol/sec/mg]/CS activity), due to a decreased CS activity (158 ± 39 vs. 129 ± 25 mU/mg dw.). No differences were observed in ROS production (per mg of tissue or when normalized to CS activity). Furthermore, the protein content for catalase was increased while superoxide dismutase and glutathione peroxidase remained unaffected. These findings were accompanied by an impaired glucose tolerance after the bed rest period (Matsuda index: 12 ± 6 vs. 9 ± 5). The change in intrinsic mitochondrial respiratory capacity could be an early indication in the development of impaired glucose tolerance. The increased catalase protein content might explain that no change was seen in ROS production after 4 days of bed rest. Whether these findings can be extrapolated to lifestyle-dependent decrements in physical activity and the development of type-2-diabetes remains unknown.nd the development of type-2-diabetes remains unknown.)
Hards 2018 Proc Natl Acad Sci U S A + (Bedaquiline (BDQ), an inhibitor of the myc … Bedaquiline (BDQ), an inhibitor of the mycobacterial F1Fo-ATP synthase, has revolutionized the antitubercular drug discovery program by defining energy metabolism as a potent new target space. Several studies have recently suggested that BDQ ultimately causes mycobacterial cell death through a phenomenon known as uncoupling. The biochemical basis underlying this, in BDQ, is unresolved and may represent a new pathway to the development of effective therapeutics. In this communication, we demonstrate that BDQ can inhibit ATP synthesis in ''Escherichia coli'' by functioning as a H+/K+ ionophore, causing transmembrane pH and potassium gradients to be equilibrated. Despite the apparent lack of a BDQ-binding site, incorporating the ''E. coli'' Fo subunit into liposomes enhanced the ionophoric activity of BDQ. We discuss the possibility that localization of BDQ at F1Fo-ATP synthases enables BDQ to create an uncoupled microenvironment, by antiporting H+/K+ Ionophoric properties may be desirable in high-affinity antimicrobials targeting integral membrane proteins.t;+/K+ Ionophoric properties may be desirable in high-affinity antimicrobials targeting integral membrane proteins.)
Teulier 2016 Proc Biol Sci + (Bees are thought to be strict users of car … Bees are thought to be strict users of carbohydrates as metabolic fuel for flight. Many insects, however, have the ability to oxidize the amino acid proline at a high rate, which is a unique feature of this group of animals. The presence of proline in the haemolymph of bees and in the nectar of plants led to the hypothesis that plants may produce proline as a metabolic reward for pollinators. We investigated flight muscle metabolism of hymenopteran species using high-resolution respirometry performed on permeabilized muscle fibres. The muscle fibres of the honeybee, ''Apis mellifera'', do not have a detectable capacity to oxidize proline, as those from the migratory locust, ''Locusta migratoria'', used here as an outgroup representative. The closely related bumblebee, ''Bombus impatiens'', can oxidize proline alone and more than doubles its respiratory capacity when proline is combined with carbohydrate-derived substrates. A distant wasp species, ''Vespula vulgaris'', exhibits the same metabolic phenotype as the bumblebee, suggesting that proline oxidation is common in hymenopterans. Using a combination of mitochondrial substrates and inhibitors, we further show that in ''B. impatiens'', proline oxidation provides reducing equivalents and electrons directly to the electron transport system. Together, these findings demonstrate that some bee and wasp species can greatly enhance the oxidation of carbohydrates using proline as fuel for flight.© 2016 The Author(s).as fuel for flight. © 2016 The Author(s).)
Shick 1988 Amer Zool + (Behaviors to conserve water during interti … Behaviors to conserve water during intertidal exposure at the same time impair respiratory gas exchange, so that observed responses to emersion may reflect compromises between these incompatible needs. Behavioral isolation of the tissues from air results in the complete or partial reliance on anoxic energy metabolism, which is most reliably measured directly as heat dissipation. Combined direct calorimetry and indirect calorimetry (respirometry) enable the partitioning of total metabolic heat dissipation into its aerobic and anoxic components, which may vary according to physical and biological factors. The mussel ''Mytilus edulis'' is tolerant of anoxia and saves water and energy during aerial exposure in its rocky intertidal habitat by closing its shell valves and becoming largely anoxic. Like most suspension feeders in this habitat, its compensation for reduced feeding time involves energy conservation; there is little evidence for energy supplementation such as increases in feeding rate or absorption efficiency. Ammonia production continues during aerial exposure and is involved in acid-base balance in the hemolymph and mantle cavity fluid. Infaunal cockles (''Cardium edule'') and mussels (''Geukensia demissa'') gape their shell valves, remain largely aerobic and have high rates of heat dissipation during intertidal exposure, a response which appears related to the lower desiccation potential and exploitation of richer trophic resources in their soft-sediment habitats. The variable expansion of the symbiotic sea anemone ''Anthopleura elegantissima'' reflects interaction among the responses to desiccation, irradiance and continued photosynthesis by its zooxanthellae during exposure to air. its zooxanthellae during exposure to air.)
Mayeur 2013 PhD Thesis + (Being small size at birth from malnutritio … Being small size at birth from malnutrition is associated with an increasedrisk to develop type 2 diabetes and cardiovascular and metabolic diseases in adulthood.The placental capacity to supply adequate amount of nutrients and oxygen to the fetusrepresents one of the main determiner of the fetal growth. Despite its critical roles duringprenatal development, few studies have investigated the effects of maternal diet on theplacental physiology and functions. Our aim was to explore the placental adaptive proteomicprocesses implicated in response to a maternal suboptimal nutrition.Rat term placentas from 70% food-restricted(FR30) mothers were used for a proteomic screen. Placental mitochondrial functions wereevaluated using molecular and functional approaches and ATP production was measured.RESULTS – FR30 drastically reduced both placental and fetal weights. FR30 placentasdisplayed 14 identified proteins differentially expressed, including several mitochondrialproteins suggesting specific alterations of these organelles. FR30 induced a marked increaseof placental mtDNA content and changes in mitochondrial functions including modulation ofthe expression of numerous genes implicated in both mitochondrial biogenesis andbioenergetic pathways. Mitochondria under FR30 conditions showed higher oxygenconsumption but fail to maintain their critical ATP production.We provide first evidence that maternal suboptimal nutrition inducesmitochondrial abnormalities in the placenta of growth-restricted fetuses. Although maternalcalorie restriction induces mitochondrial adaptive processes such as an increase of bothmitochondrial biogenesis and bioenergetic efficiency; placental ATP production wasdrastically reduced. This disturbance may be implicated in reduction of the placental capacityto actively transport nutrients that may strengthen the effect of maternal undernutrition on thedevelopment of the fetus. Our data suggest that placental mitochondrial defects may beimplicated, at least in part, in pathologies of feto-placental growth., in pathologies of feto-placental growth.)
NCD-RisC 2016 Elife + (Being taller is associated with enhanced l … Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95 % credible interval 17.5-22.7) and 16.5 cm (13.3-19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8-144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.ntial changes in the ranking of countries.)
Pena-Corona 2023 Front Pharmacol + (Being the first or second cause of death w … Being the first or second cause of death worldwide, cancer represents the most significant clinical, social, and financial burden of any human illness. Despite recent progresses in cancer diagnosis and management, traditional cancer chemotherapies have shown several adverse side effects and loss of potency due to increased resistance. As a result, one of the current approaches is on with the search of bioactive anticancer compounds from natural sources. Neopeltolide is a marine-derived macrolide isolated from deep-water sponges collected off Jamaica's north coast. Its mechanism of action is still under research but represents a potentially promising novel drug for cancer therapy. In this review, we first illustrate the general structural characterization of neopeltolide, the semi-synthetic derivatives, and current medical applications. In addition, we reviewed its anticancer properties, primarily based on in vitro studies, and the possible clinical trials. Finally, we summarize the recent progress in the mechanism of antitumor action of neopeltolide. According to the information presented, we identified two principal challenges in the research, i) the effective dose which acts neopeltolide as an anticancer compound, and ii) to unequivocally establish the mechanism of action by which the compound exerts its antiproliferative effect.pound exerts its antiproliferative effect.)
Shaikh 2014 Circulation + (Bendavia is a cell permeable, mitochondria … Bendavia is a cell permeable, mitochondria-targeting peptide currently being tested in clinical trials for acute coronary syndromes, heart failure, and renal disease. In a series of studies, we have shown that Bendavia reduces cellular injury by targeting the mitochondrial inner membrane. In particular, Bendavia targets cardiolipin, a mitochondrial phospholipid that acts as “glue” to hold respiratory protein complex subunits together. In this study, we tested the hypothesis that Bendavia would improve post-ischemic mitochondrial function by sustaining native respiratory protein complexes. We utilized blue native gels (non-denaturing conditions) alongside high-resolution respirometry in permeabilized myocardial fibers to directly link changes in protein complexes to mitochondrial function. Rat hearts were subjected to ischemia-reperfusion (I/R) with or without 1nM Bendavia perfusion beginning at the onset of reperfusion. The native expression of mitochondrial Complexes III and V were significantly reduced after I/R, and were restored with Bendavia (see Figure). The appearance of degradation bands was also noted in hearts after I/R, and these products of protein complex breakdown were also significantly reduced with Bendavia treatment. Respirometry studies in permeabilized ventricular fibers showed lower Complex I-dependent respiration after I/R (208±19 v 42±9 pmol O2/mg*s) in control v I/R, respectively; ''p''<0.05. Complex II-dependent respiration was also suppressed (753±41 v 168±13 pmol/mg*s in control versus I/R; ''p''<0.05). Treatment with Bendavia led to significantly improved Complexes I- (100±13pmol O2/mg*s) and II-dependent (334±63pmol O2/mg*s) respiration (''p''<0.05 versus untreated IR for both). Taken together, these data indicate that Bendavia is protecting myocardium by preserving native mitochondrial respiratory complexes and sustaining mitochondrial function.ry complexes and sustaining mitochondrial function.)
Brown DA 2014 Abstract MiP2014 + (Bendavia is a cytoprotective mitochondria- … Bendavia is a cytoprotective mitochondria-targeting peptide [1-4], currently being tested in the EMBRACE-STEMI trial for reducing injury during acute coronary syndromes. We previously showed that the cardioprotective effects of Bendavia involved improving cardiolipin-dependent mitochondrial membrane fluidity. As membrane fluidity influences the ability of proteins to assemble, we hypothesized that a consequence of augmented membrane fluidity would be higher expression of mitochondrial respiratory supercomplexes.Rat hearts (''N''=42) were subjected to ischemia-reperfusion (I/R) with our without 1 nM Bendavia perfusion, beginning at the onset of reperfusion. Left ventricular tissue was split into one of two study arms: 1. Supercomplex expression using blue-native gel electrophoresis (BN-PAGE), or 2. High-resolution respirometry using permeabilized ventricular fibers. For BN-PAGE studies, respiratory supercomplex bands were decreased with I/R, and restored with Bendavia (Fig. 1). High-resolution respirometry studies indicated suppressed Complex I-dependent respiration after I/R (208±19 v 42±9 pmol O2∙s-1.mg-1) in control v I/R, respectively; ''P''<0.05. Complex II-dependent respiration was also lower (753±41 v 168±13 pmol∙s-1∙mg-1 in control versus I/R; ''P''<0.05). Perfusion with Bendavia during reperfusion significantly increased Complex I- (100±13 pmol O2∙s-1.mg-1) and II-dependent (334±63 pmol O2∙s-1.mg-1) respiration (''P''<0.05 versus untreated IR for both). Taken together, these data suggest that Bendavia’s protective mechanism of action involves preserving supercomplex-dependent mitochondrial function during cardiac reperfusion.both). Taken together, these data suggest that Bendavia’s protective mechanism of action involves preserving supercomplex-dependent mitochondrial function during cardiac reperfusion.)
Felser 2014 Toxicology II + (Benzbromarone is an uricosuric structurall … Benzbromarone is an uricosuric structurally related to amiodarone and a known mitochondrial toxicant. The aim of the current study was to improve our understanding in the molecular mechanisms of benzbromarone-associated hepatic mitochondrial toxicity. In HepG2 cells and primary human hepatocytes, ATP levels started to decrease in the presence of 25-50 μM benzbromarone for 24-48 h, whereas cytotoxicity was observed only at 100 μM. In HepG2 cells, benzbromarone decreased the mitochondrial membrane potential starting at 50 μM following incubation for 24 h. Additionally, in HepG2 cells, 50 μM benzbromarone for 24 h induced mitochondrial uncoupling,and decreased mitochondrial ATP turnover and maximal respiration. This was accompanied by an increased lactate concentration in the cell culture supernatant, reflecting increased glycolysis as a compensatory mechanism to maintain cellular ATP. Investigation of the electron transport chain revealed a decreased activity of all relevant enzyme complexes. Furthermore, treatment with benzbromarone was associated with increased cellular ROS production, which could be located specifically to mitochondria. In HepG2 cells and in isolated mouse liver mitochondria, benzbromarone also reduced palmitic acid metabolism due to an inhibition of the long-chain acyl CoA synthetase. In HepG2 cells, benzbromarone disrupted the mitochondrial network, leading to mitochondrial fragmentation and a decreased mitochondrial volume per cell. Cell death occurred by both apoptosis and necrosis. The study demonstrates that benzbromarone not only affects the function of mitochondria in HepG2 cells and human hepatocytes, but is also associated with profound changes in mitochondrial structure which may be associated with apoptosis.re which may be associated with apoptosis.)
Van der Kooij 2018 Mol Psychiatry + (Benzodiazepines can ameliorate social dist … Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines' effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high-anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions.t for anxiety-related social dysfunctions.)
Vinogradov 2005 Biochemistry (Mosc) + (Besides major NADH-, succinate-, and other … Besides major NADH-, succinate-, and other substrate oxidase reactions resulting in four-electron reduction of oxygen to water, the mitochondrial respiratory chain catalyzes one-electron reduction of oxygen to superoxide radical O(2)(-.) followed by formation of hydrogen peroxide. In this paper the superoxide generation by Complex I in tightly coupled bovine heart submitochondrial particles is quantitatively characterized. The rate of superoxide formation during Deltamu(H(+))-controlled respiration with succinate depends linearly on oxygen concentration and contributes approximately 0.4% of the overall oxidase activity at saturating (0.25 mM) oxygen. The major part of one-electron oxygen reduction during succinate oxidation (approximately 80%) proceeds via Complex I at the expense of its Deltamu(H(+))-dependent reduction (reverse electron transfer). At saturating NADH the rate of O(2)(-.) formation is substantially smaller than that with succinate as the substrate. In contrast to NADH oxidase, the rate-substrate concentration dependence for the superoxide production shows a maximum at low (approximately 50 microM) concentrations of NADH. NAD+ and NADH inhibit the succinate-supported superoxide generation. Deactivation of Complex I results in almost complete loss of its NADH-ubiquinone reductase activity and in increase in NADH-dependent superoxide generation. A model is proposed according to which complex I has two redox active nucleotide binding sites. One site (F) serves as an entry for the NADH oxidation and the other one (R) serves as an exit during either the succinate-supported NAD+ reduction or superoxide generation or NADH-ferricyanide reductase reaction.n or NADH-ferricyanide reductase reaction.)
Martinez 2015 Thesis + (Besides of the 23 chromosome pairs located … Besides of the 23 chromosome pairs located in the nucleous (nDNA), the human genome also includes many DNA molecules placed in mitochondria and known as mitochondrial DNA (mtDNA). mtDNA encodes 13 subunits very important for the oxidative phosphorylation system (OXPHOS) and RNAs required for its expression. Because of its location and genetic particularities, mtDNA accumulates mutations faster than nDNA. Many of these mutations result into a serious disease. The construction of cellular models are the key to study these mutations.In his work we used the cell line HepG2, beacause its utility in ''in vitro'' studies. We studied their differentiation into mature hepatocytes and tried to remove its mtDNA to build transmitochondrial cell lines.NA to build transmitochondrial cell lines.)
Kuznetsov 2022 Antioxidants (Basel) + (Besides their main function for energy pro … Besides their main function for energy production in form of ATP in processes of oxidative phosphorylation (OxPhos), mitochondria perform many other important cellular functions and participate in various physiological processes that are congregated. For example, mitochondria are considered to be one of the main sources of reactive oxygen species (ROS) and therefore they actively participate in the regulation of cellular redox and ROS signaling. These organelles also play a crucial role in Ca2+ signaling and homeostasis. The mitochondrial OxPhos and their cellular functions are strongly cell/tissue specific and can be heterogeneous even within the same cell, due to the existence of mitochondrial subpopulations with distinct functional and structural properties. However, the interplay between different functions of mitochondria is not fully understood. The mitochondrial functions may change as a response to the changes in the cellular metabolism (signaling in). On the other hand, several factors and feedback signals from mitochondria may influence the entire cell physiology (signaling out). Numerous interactions between mitochondria and the rest of cell, various cytoskeletal proteins, endoplasmic reticulum (ER) and other cellular elements have been demonstrated, and these interactions could actively participate in the regulation of mitochondrial and cellular metabolism. This review highlights the important role of the interplay between mitochondrial and entire cell physiology, including signaling from and to mitochondria.luding signaling from and to mitochondria.)
Rose 2019 Adis + (Best known for their role in generating ad … Best known for their role in generating adenosine triphosphate (ATP) through oxidative phosphorylation, mitochondria are responsible for a wide variety of vital cellular processes including apoptosis, maintenance of calcium homeostasis, redox signaling, steroid synthesis, and lipid metabolism. The mitochondria are dynamic organelles, responding to changing cellular physiology, nutrient availability, and energy demands by changing in function as well as shape, size, distribution, and number. Given the many important roles of the mitochondria for normal cellular function, it is not surprising that mitochondrial dysfunction is involved in a wide variety of diseases and medical disorders. Despite several mechanisms to combat the leakage of electrons that accompanies electron transfer during the process of oxidative phosphorylation, mitochondria are the primary producers of reactive oxygen species (ROS) in most cell types. Given the importance of mitochondria in health and disease, the effects of the antioxidant and glutathione precursor, N-acetylcysteine (NAC), on mitochondrial function have been examined in many studies of a wide variety of medical conditions. The purpose of this review is to conduct a systematic review of the literature on the effects of NAC on mitochondrial metabolism.ffects of NAC on mitochondrial metabolism.)
Schoettl 2015 Fatty Acid Oxidation O2k-Network Discussion Forum + (Beta oxidation in adipocytes (white and brown), HEK293 cells, isolated mitochondria from liver, adipocytes, brain, etc.)
Mitochondrial Interest Group 2014 + (Bethesda, MD, US [http://sigs.nih.gov/mito … Bethesda, MD, US [http://sigs.nih.gov/mito/Pages/default.aspx Mitochondrial Interest Group] A Mitochondrial Etiology of Metabolic and Degenerative Diseases Cancer and Ageing - lecture by Dr. Wallace and Transformational Medicine in the Mitochondrial Age Symposium.dicine in the Mitochondrial Age Symposium.)
Escoll 2019 Immunometabolism + (Beyond oxidative phosphorylation (OXPHOS), … Beyond oxidative phosphorylation (OXPHOS), mitochondria have also immune functions against infection, such as the regulation of cytokine production, the generation of metabolites with antimicrobial proprieties and the regulation of inflammasome-dependent cell death, which seem in turn to be regulated by the metabolic status of the organelle. Although OXPHOS is one of the main metabolic programs altered during infection, the mechanisms by which pathogens impact the mitochondrial electron transport chain (ETC) complexes to alter OXPHOS are not well understood. Similarly, how changes on ETC components affect infection is only starting to be characterized. Herein we summarize and discuss the existing data about the regulation of ETC complexes and super-complexes during infection, in order to shed some light on the mechanisms underlying the regulation of the mitochondrial OXPHOS machinery when intracellular pathogens infect eukaryotic host cells.ar pathogens infect eukaryotic host cells.)
Franko 2016 Diabetes + (Bezafibrate (BEZ), a pan activator of pero … Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in streptozotocin (STZ)-treated mice, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.t for profit, and the work is not altered.)
NTS/INA Meeting 2017 Florianopolis Brazil + (Biennial Meeting on Metabolic derangements predisposing to neurotoxicity and neurodegenerative disease, Florianopolis, Brazil.)
Zhao 2021 Trends Cancer + (Biguanides are a class of antidiabetic dru … Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its toxicity. Findings from retrospective epidemiological studies in diabetic populations and preclinical laboratory models have demonstrated that biguanides possess antitumor activities that suggest their repurposing for cancer prevention and treatment. However, a better understanding of how these biguanides behave as antitumor agents is needed to guide their improved applications in cancer therapy, spurring increased interest in their pharmacology. Here, we present evidence for proposed mechanisms of action related to their antitumor activity, including their effects on central carbon metabolism in cancer cells and immune-modulating activity, and then review progress on biguanide repurposing in cancer therapeutics and the possible re-evaluation of phenformin as a cancer therapeutic agent. phenformin as a cancer therapeutic agent.)
Schwarzkopf 2013 Pharmazie + (Bilobalide, an active constituent of Ginkg … Bilobalide, an active constituent of Ginkgo biloba, is known to have neuroprotective properties, but its mode of action remains unclear. In this study, bilobalide significantly reduced brain damage in mice (indicated by TTC staining) when given before transient middle cerebral artery occlusion (tMCAO). As measured by microdialysis in the ischemic striatum, local perfusion with bilobalide (10 microM) reduced ischemia-induced glutamate release by 70% while glucose levels were not affected. Mitochondria isolated from ischemic brain showed a decrease of respiration compared to non-ischemic controls. Treatment with bilobalide (10 mg/kg) before tMCAO improved respiratory capacity of complex I significantly when measured ex vivo. In addition, mitochondrial swelling induced ex vivo by calcium was used to estimate opening of the mitochondrial permeability transition pore. In this assay, the changes induced by tMCAO were completely reversed when mice had received pretreatment with bilobalide. We conclude that neuroprotection by bilobalide involves a mechanism in which the drug reverses ischemia-induced changes in mitochondria, leading to a reduction of glutamate release.ading to a reduction of glutamate release.)
Garlid AO 2012 Abstract Bioblast + (Binding of cardiac glycosides to the Na,K- … Binding of cardiac glycosides to the Na,K-ATPase has two effects: increased contractility (inotropy) and cardioprotection against ischemia-reperfusion injury [1]. Cardioprotection is mediated by caveolar vesicles (signalosomes) that bud off the plasma membrane, move to mitochondria, and use a terminal kinase to phosphorylate an outer membrane protein. This activates inner membrane PKCεs, causing opening of the mitochondrial ATP-sensitive K+ channel ([[Mitochondrial ATP-sensitive K+ channel|mtKATP]]) and inhibition of the mitochondrial permeability transition (mtPT). These events are assayed ''in vitro'' using purified signalosomes from treated hearts and mitochondria from untreated hearts [2]. The terminal kinase of GPCR signalosomes is PKG [2]; however PKG does not mediate cardioprotection by [[ouabain]], so we set out to determine the terminal kinases used by the ouabain signalosome. Rat hearts perfused with ouabain yielded a signalosome fraction that was caveolar in nature and enriched with caveolins 1 and 3, Src, PKCε and the α-1-subunit of the Na+,K+-ATPase. Electron microscopy of purified signalosomes revealed vesicles approximately 140 nM in diameter that were found by immunogold labeling to be decorated with caveolin-3. Ouabain signalosomes from heart opened mtKATP in mitochondria isolated from untreated hearts and liver. The terminal kinases of the ouabain signalosome are Src and PKCε, which together phosphorylated an endogenous outer membrane p38MAPK. We conclude (1) that ouabain cardioprotection utilizes the signalosome mechanism; (2) that the terminal kinases acting on mitochondria are Src and PKCε, (3) that this is a general mechanism of cell signaling, given that signalosomes from rat heart open mtKATP in rat liver mitochondria. (4) that ouabain cardioprotection acts via a mitochondrial p38 MAPK.Digitalis has been used in the treatment of heart failure since 1785. It was thought for many years that its efficacy was due to its positive inotropic effect. This may not be the case. Cardioprotection in both rat and rabbit is seen with concentrations of ouabain that have no inotropic effect.# [http://www.ncbi.nlm.nih.gov/pubmed/17306295 Pasdois P, Beauvoit B, Costa AD, Vinassa B, Tariosse L, Bonoron-Adèle S, Garlid KD, Dos Santos P (2007) Sarcoplasmic ATP-sensitive potassium channel blocker HMR1098 protects the ischemic heart: implication of calcium, Complex I, reactive oxygen species and mitochondrial ATPsensitive potassium channel. J Mol Cell Cardiol 42: 631-642.]# [http://www.ncbi.nlm.nih.gov/pubmed/19118560 Garlid KD, Costa AD, Quinlan CL, Pierre SV, Dos Santos P (2009) Cardioprotective signaling to mitochondria. J Mol Cell Cardiol 46: 858-866. Open Access]e SV, Dos Santos P (2009) Cardioprotective signaling to mitochondria. J Mol Cell Cardiol 46: 858-866. Open Access])
Gnaiger 2022 Abstract Bioblast-eds + (Bioblast 2022 is a follow-up of Bioblast 2 … Bioblast 2022 is a follow-up of Bioblast 2012 [1] and the first life conference linked to the journal ''Bioenergetics Communications'' [2]. It can be seen in the line of MiP''conferences'' of the Mitochondrial Physiology Society [3], which was founded at the 3rd MiP''conference'' in 2003 [4]. The last one took place in 2019 in Belgrade, RS within the COST Action MitoEAGLE [5]. The MitoEAGLE Summit was prevented from happening by the pandemic lockdown. Instead, the MitoEAGLE Consortium of 666 coauthors completed the first publication in ''Bioenergetics Communications'' [6]. In the tradition of Bioblast and MiP [1,7], Bioblast 2022 is presented with the beauty of Odra Noel's ''MiPArt'' and is honored by her presence at the conference. We celebrate 30 years Oroboros Instruments. As a follow-up of the MitoEAGLE project [8], the MiP''society'' and the Oroboros Ecosystem are the drivers of ''Bioenergetics Communications''. The endosymbiotic theories link the mitochondria and plastids to their free-living ancestors. Together, these are the bioblasts in spotlight of bioenergetics. Bioblasts and interactions with their hosts are the topics of ''Bioenergetics Communications'', inaugurating the concept of ''Living Communications''. # Gnaiger E, Meissner B, Laner V, eds (2012) Bioblast 2012: Mitochondrial Competence. https://bioblast.at/index.php/MiPNet17.12_Bioblast_2012# Bioenergetics Communications BEC - https://www.bioenergetics-communications.org/index.php/bec/index# Mitochondrial Physiology Society - https://www.mitophysiology.org/index.php/Mitochondrial_Physiology_Society # Gnaiger E, Renner K, eds (2003) 3rd Conference on Mitochondrial Physiology. Schröcken, Austria, Sept 2003. https://www.mitophysiology.org/index.php/MiPNet08.10_MiP2003# Lalic Nebojsa, Krako Jakovljevic Nina (2019) 14th Conference on Mitochondrial Physiology: Mitochondrial function: changes during life cycle and in noncommunicable diseases - COST MitoEAGLE perspectives and MitoEAGLE WG and MC Meeting. https://www.mitophysiology.org/index.php/MiP2019/MitoEAGLE_Belgrade_RS# Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. https://doi.org/10.26124/bec:2020-0001.v1 # Gnaiger E (2010) Seven years Mitochondrial Physiology Society and a welcome to MiP2010: Bioblasts – the aliens with permanent residence in our cells. - https://wiki.bioblast.at/index.php/Gnaiger_2010_Abstract_MiP2010# COST Action CA15203 (2016-2021): MitoEAGLE - https://mitoeagle.org/index.php/MitoEAGLE16-2021): MitoEAGLE - https://mitoeagle.org/index.php/MitoEAGLE )
Gnaiger 2014 Abstract MiP2014 + (Biochemical '''cell ergometry''' aims at m … Biochemical '''cell ergometry''' aims at measurement of ''J''O2,max (compare ''V''O2,max in exercise ergometry of humans and animals) of cell respiration linked to phosphorylation of ADP to ATP. The corresponding [[OXPHOS-capacity]] is based on saturating concentrations of ADP, [ADP]*, and inorganic phosphate, [Pi]*, available to the mitochondria. This is metabolically opposite to uncoupling respiration, which yields [[ET-capacity]]. The OXPHOS state can be established experimentally by selective [[permeabilized cells |permeabilization of cell membranes]] with maintenance of intact mitochondria, titrations of ADP and Pi to evaluate kinetically saturating conditions, and establishing fuel substrate combinations which reconstitute physiological [[TCA cycle]] function.[[TCA cycle]] function.)
Kunz 1999 J Neurochem + (Biochemical micromethods were used for the … Biochemical micromethods were used for the investigation of changes in mitochondrial oxidative phosphorylation associated with cytochrome c oxidase deficiency in brain cortex from Movbr (mottled viable brindled) mice, an animal model of Menkes’ copper deficiency syndrome. Enzymatic analysis of cortex homogenates from Movbr mice showed an approximately twofold decreasein cytochrome c oxidase and a 1.4-fold decrease in NADH:cytochrome c reductase activities as compared with controls. Assessment of mitochondrial respiratory function was performed using digitonin-treated homogenates of the cortex, which exhibited the main characteristics of isolated brain mitochondria. Despite the substantial changes in respiratory chain enzyme activities, no significant differences were found in maximal pyruvate or succinate oxidation rates of brain cortex homogenates from Movbr and control mice. Inhibitor titrations wereused to determine flux control coefficients of NADH:CoQ oxidoreductase and cytochrome c oxidase on the rate of mitochondrial respiration. Application of amobarbital to titrate the activity of NADH:CoQ oxidoreductase showed very similar flux control coefficients for control and mutant animals. Alternately, titration of respiration with azide revealed for Movbr mice significantly sharper inhibition curves than for controls, indicating a more than twofold elevated flux control coefficient of cytochrome c oxidase. Owing to the reserve capacity of respiratory chain enzymes, the reported changes in activities do not seem to affect whole-brain high-energy phosphates, as observed in a previous study using 31P NMR.bserved in a previous study using 31P NMR.)
Von Brand 1966 Academic Press + (Biochemistry of Parasites presents the bio … Biochemistry of Parasites presents the biochemical aspects of parasitology. The topics covered in the book include inorganic substances; carbohydrate relationships of parasites; parasitic metabolism of carbohydrates and transport mechanisms; distribution of lipids in the bodies of parasites; and disturbances in the host's protein metabolism during parasitic infections.in metabolism during parasitic infections.)
Walczak 2018 FASEB J + (Bioenergetic failure, oxidative stress, an … Bioenergetic failure, oxidative stress, and changes in mitochondrial morphology are common pathologic hallmarks of amyotrophic lateral sclerosis (ALS) in several cellular and animal models. Disturbed mitochondrial physiology has serious consequences for proper functioning of the cell, leading to the chronic mitochondrial stress. Mitochondria, being in the center of cellular metabolism, play a pivotal role in adaptation to stress conditions. We found that mitochondrial dysfunction and adaptation processes differ in primary fibroblasts derived from patients diagnosed with either sporadic or familial forms of ALS. The evaluation of mitochondrial parameters such as the mitochondrial membrane potential, the oxygen consumption rate, the activity and levels of respiratory chain complexes, and the levels of ATP, reactive oxygen species, and Ca2+ show that the bioenergetic properties of mitochondria are different in sporadic ALS, familial ALS, and control groups. Comparative statistical analysis of the data set (with use of principal component analysis and support vector machine) identifies and distinguishes 3 separate groups despite the small number of investigated cell lines and high variability in measured parameters. These findings could be a first step in development of a new tool for predicting sporadic and familial forms of ALS and could contribute to knowledge of its pathophysiology.ibute to knowledge of its pathophysiology.)
Khan 2015 Abstract MiPschool Cape Town 2015 + (Bioenergetic health index (BHI) profiling … Bioenergetic health index (BHI) profiling is an emerging concept in the field of mitochondrial research [1]. In general, bioenergetics is the study of balance between energy intake and energy utilization for life sustaining processes. Mitochondrion serves as an early warning signal of bioenergetics crisis in patient populations. Any changes in bioenergetics are the first signal to determine the progression of mitochondrial disorders that are complex and multifactorial. In order to achieve the above, the platelets from the patient’s blood samples were extracted and subjected to high throughput assays such as XF Extracellular Flux Analyzer, BHI can be calculated to represent the patient’s composite mitochondrial profile by monitoring the bioenergetic health of immune cells such as monocytes, lymphocytes, neutrophils and platelets from blood [2]. This approach can be a step towards personalized cell based measurements to quantify bioenergetic health index. The study will be discussed in detail later.e study will be discussed in detail later.)
Kaambre 2013 Front Physiol + (Bioenergetic profiling of cancer cells is … Bioenergetic profiling of cancer cells is of great potential because it can bring forward new and effective therapeutic strategies along with early diagnosis. Metabolic Control Analysis (MCA) is a methodology that enables quantification of the flux control exerted by different enzymatic steps in a metabolic network thus assessing their contribution to the system's function. Our main goal is to demonstrate the applicability of MCA for in situ studies of energy metabolism in human breast and colorectal cancer cells as well as in normal tissues. We seek to determine the metabolic conditions leading to energy flux redirection in cancer cells. A main result obtained is that the adenine nucleotide translocator exhibits the highest control of respiration in human breast cancer thus becoming a prospective therapeutic target. Additionally, we present evidence suggesting the existence of mitochondrial respiratory supercomplexes that may represent a way by which cancer cells avoid apoptosis. The data obtained show that MCA applied in situ can be insightful in cancer cell energetic research.ightful in cancer cell energetic research.)
Bioenergetics Exhibition - Art meets Gentle Science + (Bioenergetics - Art meets Gentle Science in Sickness and in Health. A [[Gentle Science]] project initiated by [[Iyer S |Shilpa Iyer]]. Science Museum of Virginia, Richmond VA, US.)
Truu 2017 Abstract IOC122 + (Bioenergetics is a fast growing field in c … Bioenergetics is a fast growing field in cancer research, where many promising outcomes could provide targeted cancer treatment. Energy metabolism specific literature is characterized by many contradictions, concluding that cancer cells metabolize their increased glucose uptake via glycolysis rather than more energy efficient oxidative phosphorylation (OXPHOS). Furthermore, the majority of these conclusions are the outcome of only ''in vitro'' studies on cell culture models, without taking into consideration the factors arising from the tumor microenvironment giving significant effects ''in vivo''. We have conducted quantitative cellular respiration analysis on normal colon tissue, colorectal cancer (HCC) clinical tissue samples and CaCo-2 cell cultures. Our results show that HCC is not a fully glycolytic tumor and OXPHOS system might be the main source of ATP. Comparing healthy colon, HCC tissue and CaCo-2 cells, we found elevated rates of maximal ADP-activated respiration and greater activity of respiratory complex (C) II over CI in both HCC and CaCo-2 cells, whereas the opposite result in healthy tissue was present. These results indicate that the bioenergetic profile of Caco-2 cells corresponds generally to HCC tissue. Further research is in progress to generate a full cancer development model consisting of cell cultures, clinical polyps and malignant versus healthy tissue samples.d malignant versus healthy tissue samples.)
Huete-Ortega 2018 AlgaEurope2018 + (Bioenergetics is the study of energy trans … Bioenergetics is the study of energy transformations in cells, mitochondria, and chloroplasts as a basis to perform biochemical work. In algal chloroplasts solar energy is acquired and assimilated through photosynthesis to synthesize the organic matter required for growth, which is associated with production of oxygen, while mitochondrial respiration consumes oxygen to transform organic matter into the chemical energy that fuels cellular activity. Energetic coupling between chloroplasts and mitochondria has been described in algae. For example, mitochondrial physiology is involved in mitigating light stress in the photosynthetic pathway or chloroplast-generated reducing equivalents replace photophosphorylation as a source of ATP in the mitochondria. Therefore, a good functionality and cross-talk between both organelles is necessary to maintain metabolic integrity. High-resolution respirometry (HRR) is widely used to assess mitochondrial respiration and other bioenergetic parameters of isolated mitochondria, cultured cells, tissue preparations and human biopsies. In the biomedical field of mitochondrial physiology and its clinical applications, studies with HRR relate to degenerative diseases and life style-linked preventive medicine. I propose to extend the experimental options of the Oroboros O2k developed by Oroboros Instruments for HRR to the study of algae bioenergetics for biotechnological purposes. Outstanding applications include: i) research on mitochondrial respiration, photosynthesis and other bioenergetic parameters in algae, including the metabolic interactions between mitochondria and chloroplasts and their effects on production of biomass and organic molecules; ii) analysis of functional alterations of algae mutants generated for biotechnology; iii) optimization of cryopreservation in algae strains used in biotechnology by diagnostic evaluation of bioenergetic functionality. evaluation of bioenergetic functionality.)
Ebanks 2022 Abstract Bioblast + (Biological ageing is one of the biggest ri … Biological ageing is one of the biggest risk factors for a range of diseases, including cancers, neurodegenerative disease, and heart disease. Mitochondrial dysfunction is associated with both ageing and diseases of ageing. As exercise is increasingly being viewed as a potential anti-ageing therapy, we sought to assess the impact of exercise on the fitness and lifespan of ''D. melanogaster''[1]. In addition, we assessed the exercise-induced changes to mitochondrial physiology through high-resolution respirometry and label-free mass spectrometry. Exercise in late life extends the lifespan of male and female ''D. melanogaster'' compared with those exercised throughout their entire lifetime. Exercise also increases Complex-II-linked respiration and upregulates the expression of proteins from the electron transfer Complexes I, III, IV.# Ebanks B, Wang Y, Katyal G, Sargent C, Ingram TL, Bowman A, Moisoi N, Chakrabarti L (2021) Exercising ''D. melanogaster'' modulates the mitochondrial proteome and physiology. The effect on lifespan depends upon age and sex. https://doi.org/10.3390/ijms222111606. https://doi.org/10.3390/ijms222111606 )
Schmidt 2021 J Biol Chem + (Biological energy transduction underlies a … Biological energy transduction underlies all physiological phenomena in cells. The metabolic systems that support energy transduction have been of great interest due to their association with numerous pathologies including diabetes, cancer, rare genetic diseases, and aberrant cell death. Commercially available bioenergetics technologies (e.g. extracellular flux analysis, high resolution respirometry, fluorescent dye kits, etc.) have made practical assessment of metabolic parameters widely accessible. This has facilitated an explosion in the number of studies exploring, in particular, the biological implications of oxygen consumption rate (OCR) and substrate level phosphorylation via glycolysis (i.e. via extracellular acidification rate (ECAR)). Though these technologies have demonstrated substantial utility and broad applicability to cell biology research, they are also susceptible to historical assumptions, experimental limitations, and other caveats that have led to premature and/or erroneous interpretations. This review enumerates various important considerations for designing and interpreting cellular and mitochondrial bioenergetics experiments, some common challenges and pitfalls in data interpretation, and some potential ‘next steps’ to be taken that can address these highlighted challenges. can address these highlighted challenges.)
Austvold 2024 Front Physiol + (Biological magnetic field sensing that giv … Biological magnetic field sensing that gives rise to physiological responses is of considerable importance in quantum biology. The radical pair mechanism (RPM) is a fundamental quantum process that can explain some of the observed biological magnetic effects. In magnetically sensitive radical pair (RP) reactions, coherent spin dynamics between singlet and triplet pairs are modulated by weak magnetic fields. The resulting singlet and triplet reaction products lead to distinct biological signaling channels and cellular outcomes. A prevalent RP in biology is between flavin semiquinone and superoxide (O2•−) in the biological activation of molecular oxygen. This RP can result in a partitioning of reactive oxygen species (ROS) products to form either O2•− or hydrogen peroxide (H2O2). Here, we examine magnetic sensing of recombinant human electron transfer flavoenzyme (ETF) reoxidation by selectively measuring O2•− and H2O2 product distributions. ROS partitioning was observed between two static magnetic fields at 20 nT and 50 μT, with a 13% decrease in H2O2 singlet products and a 10% increase in O2•− triplet products relative to 50 µT. RPM product yields were calculated for a realistic flavin/superoxide RP across the range of static magnetic fields, in agreement with experimental results. For a triplet born RP, the RPM also predicts about three times more O2•− than H2O2, with experimental results exhibiting about four time more O2•− produced by ETF. The method presented here illustrates the potential of a novel magnetic flavoprotein biological sensor that is directly linked to mitochondria bioenergetics and can be used as a target to study cell physiology.ore O2•− produced by ETF. The method presented here illustrates the potential of a novel magnetic flavoprotein biological sensor that is directly linked to mitochondria bioenergetics and can be used as a target to study cell physiology.)
Blanco 2017 Academic Press + (Biological oxidations do not take place by … Biological oxidations do not take place by direct transfer of electrons (e−) from substrate to oxygen. They are carried out in successive stages by different e− acceptors with increasing reduction potential. This allows for a stepwise release of energy and its best utilization by the cell. The respiratory chain, located in the mitochondrial inner membrane, comprises a series of H or electrons (e−) acceptors arranged according to increasing reduction potential, associated with enzymes that catalyze e− transfer. It is composed of complex I or NADH–ubiquinone reductase, complex II or succinate–ubiquinone reductase, ubiquinone or coenzyme Q, complex III or ubiquinone–cytochrome c reductase, cytochrome c, located on the outer face of inner membrane, complex IV or cytochrome oxidase. Finally 4 e− are transferred to 2 O atoms, which with 4 H+ form 2 H2O. The energy produced by the flow of e− is coupled to phosphoryl transfer, synthesizing adenosine triphosphate (ATP) from ADP in a process known as oxidative phosphorylation. Each e− pair from substrates of NAD-linked dehydrogenases generates three molecules of ATP, while substrates oxidized by FAD-dependent enzymes produce two ATP. The chemio-osmotic hypothesis explains the mechanism underlying oxidative phosphorylation. The energy generated by the flow of reducing equivalents is used to pump protons from the mitochondrial matrix outward into the inner membrane, at the site of complexes I, III, and IV. The proton gradient created across the mitochondrial inner membrane drives proton flux through the F1F0 or ATP synthase complex, which couples proton transport to phosphate addition to ADP. Compounds that reduce or eliminate the proton gradient inhibit phosphorylation. Inhibitors can block e− transfer at different levels of the respiratory chain. Rotenone, amytal, and other barbiturates act at the level of complex I; antimycin A, at complex III; and cyanide, carbon monoxide, and azide, on complex IV. Inhibitors of oxidative phosphorylation include proton and K+ ionophores, which suppress the mitochondrial electrical potential gradient, acting as uncoupling agents, and compounds, such as oligomycin, which interfere with the function of the F1F0 ATPase. Brown fat present in infants and hibernating animals has thermogenin, a protein that inhibits ATP synthesis, uncoupling mitocondrial function and contributing to maintain body temperature. Oxidative phosphorylation is mainly controlled by ADP levels. Phosphorylation at substrate level is another way to generate ATP by phosphoryl transfer from high energy metabolites.ryl transfer from high energy metabolites.)
Koch 2021 Trends Ecol Evol + (Biologists have long appreciated the criti … Biologists have long appreciated the critical role that energy turnover plays in understanding variation in performance and fitness among individuals. Whole-organism metabolic studies have provided key insights into fundamental ecological and evolutionary processes. However, constraints operating at subcellular levels, such as those operating within the mitochondria, can also play important roles in optimizing metabolism over different energetic demands and time scales. Herein, we explore how mitochondrial aerobic metabolism influences different aspects of organismal performance, such as through changing adenosine triphosphate (ATP) and reactive oxygen species (ROS) production. We consider how such insights have advanced our understanding of the mechanisms underpinning key ecological and evolutionary processes, from variation in life-history traits to adaptation to changing thermal conditions, and we highlight key areas for future research.e highlight key areas for future research.)
Biophysical Society Symposium 2015 + (Biophysical Society – Bioenergetics Subgroup Mini-Symposium, Baltimore, MD, USA)
Scaini 2015 Abstract IOC106 + (Bipolar disorder (BD) presents a complex a … Bipolar disorder (BD) presents a complex alternating clinical course withrecurrent mood changes including manic and depressive episodes. Moreover,studies show that changes in energy metabolism are involved in thepathophysiology of BD and that omega-3 (ω3) fatty acids have beneficialproperties in the central nervous system, by modulate energy metabolism.Thus, in the present study we evaluate the effect of ω3 fatty acids alone or incombination with lithium or valproate on bioenergetic parameters, namelyrespiratory complexes (CI, CII, CII–III, CIV), malate dehydrogenase, succinatedehydrogenase, citrate synthase and creatine kinase activities. We observeda significant decrease of succinate dehydrogenase, complexes II and IV andcreatine kinase activities in hippocampus of animals submitted to fenproporexadministration, as compared to the control group. Additionally, the ω3 fattyacids in combination with VPA or Li were able to reverse the decrease insuccinate dehydrogenase, complexes II and IV activities. However, thedecrease in CK activity was reversed only with ω3 fatty acids in associationwith VPA. The present findings support the idea that ω3 fatty acid plays animportant role in the modulation of energy metabolism, and exercise essentialantioxidant capacity in the central nervous system, suggesting that the ω3fatty acids may be a possible contributing in BD therapy. be a possible contributing in BD therapy.)
Moon 2012 J Korean Med Sci + (Bisphenol A (BPA) has been reported to pos … Bisphenol A (BPA) has been reported to possess hepatic toxicity. We investigated the hypothesis that BPA, below the no observed adverse effect level (NOAEL), can induce hepatic damage and mitochondrial dysfunction by increasing oxidative stress in the liver. Two doses of BPA, 0.05 and 1.2 mg/kg body weight/day, were administered intraperitoneally for 5 days to mice. Both treatments impaired the structure of the hepatic mitochondria, although oxygen consumption rate and expression of the respiratory complex decreased only at the higher dose. The hepatic levels of malondialdehyde (MDA), a naturally occurring product of lipid peroxidation, increased, while the expression of glutathione peroxidase 3 (GPx3) decreased, after BPA treatment. The expression levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) also increased. In HepG2 cells, 10 or 100 nM of BPA also decreased the oxygen consumption rate, ATP production, and the mitochondrial membrane potential. In conclusion, doses of BPA below the NOAEL induce mitochondrial dysfunction in the liver, and this is associated with an increase in oxidative stress and inflammation.ease in oxidative stress and inflammation.)
Maciocci 2019 eLife + (Blending the traditional manuscript with l … Blending the traditional manuscript with live code, data and interactive figures, we showcase a new way for researchers to tell their full story. In September 2017 eLife announced the start of the Reproducible Document Stack (RDS) project, a collaboration between Substance, Stencila and eLife to support the development of an open-source technology stack aimed at enabling researchers to publish reproducible manuscripts through online journals. Reproducible manuscripts enrich the traditional narrative of a research article with code, data and interactive figures that can be executed in the browser, downloaded and explored, giving readers a direct insight into the methods, algorithms and key data behind the published research.Today eLife, in collaboration with Substance, Stencila and Tim Errington, Director of Research ar the Center for Open Science, US, published its first reproducible article, based on one of Errington’s papers in the Reproducibility Project: Cancer Biology. This reproducible version of the article showcases some of what’s possible with the new RDS tools, and we invite researchers to explore the newly available opportunities to tell their story.ailable opportunities to tell their story.)
Tyrrell 2016 Redox Biol + (Blood based bioenergetic profiling strateg … Blood based bioenergetic profiling strategies are emerging as potential reporters of systemic mitochondrial function; however, the extent to which these measures reflect the bioenergetic capacity of other tissues is not known. The premise of this work is that highly metabolically active tissues, such as skeletal and cardiac muscle, are susceptible to differences in systemic bioenergetic capacity. Therefore, we tested whether the respiratory capacity of blood cells, monocytes and platelets, are related to contemporaneous respirometric assessments of skeletal and cardiac muscle mitochondria. 18 female vervet/African green monkeys (''Chlorocebus aethiops sabaeus'') of varying age and metabolic status were examined for this study. Monocyte and platelet maximal capacity correlated with maximal oxidative phosphorylation capacity of permeabilized skeletal muscle (R=0.75, 95% confidence interval [CI]: 0.38-0.97; R=0.51, 95%CI: 0.05-0.81; respectively), isolated skeletal muscle mitochondrial respiratory control ratio (RCR; R=0.70, 95%CI: 0.35-0.89; R=0.64, 95%CI: 0.23-0.98; respectively), and isolated cardiac muscle mitochondrial RCR (R=0.55, 95%CI: 0.22-0.86; R=0.58, 95%CI: 0.22-0.85; respectively). These results suggest that blood based bioenergetic profiling may be used to report on the bioenergetic capacity of muscle tissues. Blood cell respirometry represents an attractive alternative to tissue based assessments of mitochondrial function in human studies based on ease of access and the minimal participant burden required by these measures.Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.shed by Elsevier B.V. All rights reserved.)
Mahapatra 2024 J Gerontol A Biol Sci Med Sci + (Blood based mitochondrial bioenergetic pro … Blood based mitochondrial bioenergetic profiling is a feasible, economical, and minimally invasive approach that can be used to examine mitochondrial function and energy metabolism in human subjects. In this study, we use two complementary respirometric techniques to evaluate mitochondrial bioenergetics in both intact and permeabilized peripheral blood mononuclear cells (PBMCs) and platelets to examine sex dimorphism in mitochondrial function among older adults. Employing equal numbers of PBMCs and platelets to assess mitochondrial bioenergetics, we observe significantly higher respiration rates in female compared to male participants. Mitochondrial bioenergetic differences remain significant after controlling for independent parameters including demographic parameters (age, years of education), and cognitive parameters (mPACC5, COGDX). Our study illustrates that circulating blood cells, immune cells in particular, have distinctly different mitochondrial bioenergetic profiles between females and males. These differences should be taken into account as blood based bioenergetic profiling is now commonly used to understand the role of mitochondrial bioenergetics in human health and aging.l bioenergetics in human health and aging.)
Pignanelli 2019 Thesis + (Blood flow restriction during resistance e … Blood flow restriction during resistance exercise is an effective method for increasing muscular size and strength. However, skeletal muscle adaptations to low-load resistance exercise (LL-RE) and low-load blood flow restriction resistance exercise (LL-BFR) performed to repetition failure are lacking. Whole-body and skeletal muscle physiological outcomes were measured following 6-weeks of LL-RE and LL-BFR training to repetition failure using a within-subject design. Similar muscle strength and size outcomes occurred despite lower total exercise volume with LL-BFR. Both groups increased power output during the first-third of an endurance task and only LL-BFR training sustained a greater power output during the midpoint by 18%. Capillary contacts of type I muscle fibers increased similarly for both groups and only LL-RE training increased mitochondrial respiratory capacity by 20%. Overall, differences in muscle fatigue between LL-RE and LL-BFR may exist and are not explained by muscular strength and size or muscle microvascular and mitochondrial properties.icrovascular and mitochondrial properties.)
Lasalvia 2018 PLOS ONE + (Blood is a fluid connective tissue of huma … Blood is a fluid connective tissue of human body, where it plays vital functions for the nutrition, defense and well-being of the organism. When circulating in peripheral districts, it is exposed to some physical stresses coming from outside the human body, as electromagnetic fields (EMFs) which can cross the skin. Such fields may interact with biomolecules possibly inducing non thermal-mediated biological effects at the cellular level. In this study, the occurrence of biochemical/biological modifications in human peripheral blood lympho-monocytes exposed in a reverberation chamber for times ranging from 1 to 20 h to EMFs at 1.8 GHz frequency and 200 V/m electric field strength was investigated. Morphological analysis of adherent cells unveiled, in some of these, appearance of an enlarged and deformed shape after EMFs exposure. Raman spectra of the nuclear compartment of cells exposed to EMFs revealed the onset of biochemical modifications, mainly consisting in the reduction of the DNA backbone-linked vibrational modes. Respirometric measurements of mitochondrial activity in intact lympho-monocytes resulted in increase of the resting oxygen consumption rate after 20 h of exposure, which was coupled to a significant increase of the FoF1-ATP synthase-related oxygen consumption. Notably, at lower time-intervals of EMFs exposure (i.e. 5 and 12 h) a large increase of the proton leak-related respiration was observed which, however, recovered at control levels after 20 h exposure. Confocal microscopy analysis of the mitochondrial membrane potential supported the respiratory activities whereas no significant variations in the mitochondrial mass/morphology was observed in EMFs-exposed lympho-monocytes. Finally, altered redox homeostasis was shown in EMFs-exposed lympho-monocytes, which progressed differently in nucleated cellular subsets. These results suggest the occurrence of adaptive mechanisms put in action, likely via redox signaling, to compensate for early impairments of the oxidative phosphorylation system caused by exposure to EMFs. Overall the data presented warn for health safety of people involved in long-term exposure to electromagnetic fields, although further studies are required to pinpoint the leukocyte cellular subset(s) selectively targeted by the EMFs action and the mechanisms by which it is achieved.nd the mechanisms by which it is achieved.)
Siewiera 2022 Int J Mol Sci + (Blood platelet dysfunctions are strongly i … Blood platelet dysfunctions are strongly involved in the development of the micro- and macrovascular complications in diabetes mellitus (DM). However, the molecular causes of abnormal platelet activation in DM remain unclear. Experimental data suggests that platelet mitochondria can regulate the prothrombotic phenotype of platelets, and changes in these organelles may influence platelet activation and modify platelet responses to stimulation. The present study evaluates the impact of DM on mitochondrial respiratory parameters and blood platelet activation/reactivity in a rat model of experimental diabetes following 1, 2.5 and 5 months of streptozotocin (STZ)-induced diabetes. Moreover, a mild inhibition of the mitochondrial respiratory chain with the use of metformin under ''in vitro'' and ''in vivo'' conditions was tested as a method to reduce platelet activation and reactivity. The platelets were studied with a combination of flow cytometry and advanced respirometry. Our results indicate that prolonged exposure of blood platelets to high concentrations of glucose, as in diabetes, can result in elevated blood platelet mitochondrial respiration; this may be an effect of cell adaptation to the high availability of energy substrates. However, as these alterations occur later than the changes in platelet activation/reactivity, they may not constitute the major reason for abnormal platelet functioning in DM. Moreover, metformin was not able to inhibit platelet activation and reactivity under ''in vitro'' conditions despite causing a decrease in mitochondrial respiration. This indicates that the beneficial effect of metformin on the coagulation system observed ''in vivo'' can be related to other mechanisms than via the inhibition of platelet activation.via the inhibition of platelet activation.)
Siewiera 2021 Int J Mol Sci + (Blood platelets are considered as promisin … Blood platelets are considered as promising candidates as easily-accessible biomarkers of mitochondrial functioning. However, their high sensitivity to various stimulus types may potentially affect mitochondrial respiration and lead to artefactual outcomes. Therefore, it is crucial to identify the factors associated with platelet preparation that may lead to changes in mitochondrial respiration. A combination of flow cytometry and advanced respirometry was used to examine the effect of blood anticoagulants, the media used to suspend isolated platelets, respiration buffers, storage time and ADP stimulation on platelet activation and platelet mitochondria respiration. Our results clearly show that all the mentioned factors can affect platelet mitochondrial respiration. Briefly, (i) the use of EDTA as anticoagulant led to a significant increase in the dissipative component of respiration (LEAK), (ii) the use of plasma for the suspension of isolated platelets with MiR05 as a respiration buffer allows high electron transfer capacity and low platelet activation, and (iii) ADP stimulation increases physiological coupling respiration (ROUTINE). Significant associations were observed between platelet activation markers and mitochondrial respiration at different preparation steps; however, the fact that these relationships were not always apparent suggests that the method of platelet preparation may have a greater impact on mitochondrial respiration than the platelet activation itself.ation than the platelet activation itself.)
Nauta 2016 Thesis + (Blood vessels are crucial in the mammalian … Blood vessels are crucial in the mammalian body for the delivery of oxygen, nutrients andsignaling molecules, such as hormones, to cells and the removal of waste product from thesecells. Endothelial cells (ECs) line the entire vasculature. In the healthy body, most ECs arequiescent; the cells hardly divide. Nonetheless, the endothelium performs manyphysiological functions, such as vasoregulation by producing vasoactive factors includingnitric oxide (NO) and endothelin-1 (ET-1) required for adequate distribution of bloodbetween the tissues; formation of a barrier between blood and surrounding tissues that allowsoptimal exchange of oxygen, nutrients and hormones; hemostasis; and the recruitment ofleukocytes at sites of inflammation (3). Dysfunction of the endothelium is associated withmany diseases, such as atherosclerosis, hypertension, thrombosis and improper inflammatoryactivation of tissues; endothelial barrier dysfunction leads to vascular leakage, which isrelated to pathological conditions, including sepsis (21), acute lung injury (47), and cancer(25). Improper functioning of tissues often results in inadequate perfusion and the need foradditional blood supply. This can occur by neovascularization, a process in which endothelialcells play a central role. This thesis investigates the effect of long-term hypoxia on theresponse of endothelial cells that leads to improved vascularization.ls that leads to improved vascularization.)
Mahapatra 2018 Clin Sci (Lond) + (Blood-based bioenergetic profiling has pro … Blood-based bioenergetic profiling has promising applications as a minimally invasive biomarker of systemic bioenergetic capacity. In the present study, we examined peripheral blood mononuclear cell (PBMC) mitochondrial function and brain morphology in a cohort of African Americans with long-standing Type 2 diabetes. Key parameters of PBMC respiration were correlated with white matter, gray matter, and total intracranial volumes. Our analyses indicate that these relationships are primarily driven by the relationship of systemic bioenergetic capacity with total intracranial volume, suggesting that systemic differences in mitochondrial function may play a role in overall brain morphology.y play a role in overall brain morphology.)
Marie 2018 Cell Death Dis + (Blue light is an identified risk factor fo … Blue light is an identified risk factor for age-related macular degeneration (AMD). We investigated oxidative stress markers and mitochondrial changes in A2E-loaded retinal pigment epithelium cells under the blue-green part of the solar spectrum that reaches the retina to better understand the mechanisms underlying light-elicited toxicity.Primary retinal pigment epithelium cells were loaded with a retinal photosensitizer, AE2, to mimic aging. Using a custom-made illumination device that delivers 10 nm-wide light bands, we demonstrated that A2E-loaded RPE cells generated high levels of both hydrogen peroxide (H2O2) and superoxide anion (O2•-) when exposed to blue-violet light. In addition, they exhibited perinuclear clustering of mitochondria with a decrease of both their mitochondrial membrane potential and their respiratory activities. The increase of oxidative stress resulted in increased levels of the oxidized form of glutathione and decreased superoxide dismutase (SOD) and catalase activities. Furthermore, mRNA expression levels of the main antioxidant enzymes (SOD2, catalase, and GPX1) also decreased.Using an innovative illumination device, we measured the precise action spectrum of the oxidative stress mechanisms on A2E-loaded retinal pigment epithelium cells. We defined 415-455 nm blue-violet light, within the solar spectrum reaching the retina, to be the spectral band that generates the highest amount of reactive oxygen species and produces the highest level of mitochondrial dysfunction, explaining its toxic effect. This study further highlights the need to filter these wavelengths from the eyes of AMD patients.udy further highlights the need to filter these wavelengths from the eyes of AMD patients.)
Gnaiger 2020 APS Chicago + (Body mass excess accumulated in sedentary … Body mass excess accumulated in sedentary lifestyles leads to deceleration of running speed. How does obesity, however, cause dementia and psychological disorders? Systemic decline of mitochondrial fitness from muscle to brain links the obesogenic lifestyle to common comorbidities. mitObesity represents the world-wide leading cause of early aging, neurodegeneration, and deaths.arly aging, neurodegeneration, and deaths.)
Dagan 2013 Nutr J + (Body mass index (BMI) is more commonly use … Body mass index (BMI) is more commonly used than waist circumference as a measure of adiposity in clinical and research settings. The purpose of this study was to compare the associations of BMI and waist circumference with cardiorespiratory fitness.In a cross-sectional study of 403 healthy men and women aged 50 ± 8.8 years, BMI and waist circumference were measured. Cardiorespiratory fitness was assessed from estimated maximal O2 uptake (VO2max), as calculated from a maximal fitness test.Mean BMI (kg/m2) was 27.8 ± 3.7 and 25.5 ± 4.6; and mean waist circumference (cm) 94.1 ± 9.7 and 84.3 ± 10.4 for men and women, respectively. Both men and women reported an average of 2.5 hours of weekly sports related physical activity, and 18% were current smokers. Correlation coefficients between both BMI and waist circumference, and VO2max were statistically significant in men (r= -0.280 and r= -0.377, respectively, p>0.05 for both) and in women (r= -0.514 and r= -0.491, respectively, p>0.05 for both). In women, the contribution of BMI to the level of VO2max in a regression model was greater, while in men waist circumference contributed more to the final model. In these models, age, hours of training per week, and weekly caloric expenditure in sport activity, significantly associated with VO2max, while smoking did not.The differences observed between the sexes in the associations of BMI and waist circumference with VO2max support the clinical use of both obesity measures for assessment of cardiorespiratory fitness.res for assessment of cardiorespiratory fitness.)
Diverse Populations Collaborative Group 2005 Am J Phys Anthropol + (Body mass index (BMI, weight (kg)/height ( … Body mass index (BMI, weight (kg)/height (m)(2)) is the most widely used weight-height index worldwide. This universal use of BMI assumes that the rationale for its use is universally applicable. We examine two possible rationales for using BMI as a universal measure. The first rationale is that BMI is strongly correlated with weight, but is independent of height. The second rationale is that BMI correctly captures the relationship between weight and height, which implies that the slope of log weight regressed on log height is 2. We examined the weight-height relationship in 25 diverse population samples of men and women from the US, Europe, and Asia. The analysis included 72 subgroups with a total of 385,232 adults aged 25 years and older. Although BMI was highly correlated with weight in all studies, a significant, negative correlation between BMI and height was found in 31 out of 40 subgroups of men (r=-0.004 to -0.133) and 32 of 32 groups of women (r=-0.016 to -0.205). When log weight was regressed on log height, the 95% confidence intervals (CI) of the slopes did not include 2 in 25 out of 40 male subgroups. The summary estimate of the slopes across studies of men was 1.92 (95% CI, 1.87-1.97). For women, slopes were lower than 2 in 28 of 32 subgroups with a summary estimate of 1.45 (95% CI, 1.39-1.51). In most of the populations, BMI is not independent of height; weight does not universally vary with the square of height; and the relationship between weight and height differs significantly between males and females. The use of a single BMI standard for both men and women cannot be justified on the basis of weight-height relationships. the basis of weight-height relationships.)
Apovian 2016 Am J Manag Care + (Body mass index of 30 kg/m2< … Body mass index of 30 kg/m2 or higher is used to identify individuals with obesity. In the last 3 decades, the worldwide prevalence of obesity has increased 27.5 % for adults and 47.1 % for children. Obesity is the result of complex relationships between genetic, socioeconomic, and cultural influences. Consumption patterns, urban development, and lifestyle habits influence the prevalence of obesity. The condition may be the result of disease or pharmacologic treatment. It may also be a risk factor for the development of comorbid conditions. Persons who are obese have less school attendance, reduced earning potential, and higher healthcare costs that may result in an economic burden on society. A review of the prevalence and economic consequences of obesity is provided. Potential causes and comorbidities associated with obesity are also discussed.orbidities associated with obesity are also discussed.)