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• 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.</br></br>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.</br></br>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.</br></br>Conclusion: RexYFP is suitable for detecting the NAD(H) redox state in different cellular compartments.</br></br>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.</br></br>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.</br></br>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.</br></br>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.</br></br>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.</br></br>Conclusion: MB is able to protect against TEGDMA-induced CI damage, and might provide protective effects in resin monomer exposed cells.</br>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.</br></br>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.</br></br>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.</br></br>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.</br></br>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.</br></br>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.</br></br>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.</br></br><small>Copyright © 2019 Elsevier B.V. All rights reserved.</small>The possible physiological consequences of this finding are discussed. <small>Copyright © 2019 Elsevier B.V. All rights reserved.</small>)
• 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. </br></br>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]. </br></br>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 and</br>cardioskeletal myopathy resulting from mutations in the tafazzin (taz) gene. The present study</br>characterized skeletal muscle mitochondrial function and exercise capacity of a taz shRNA</br>mouse model of Barth Syndrome (90% taz-deficient), and examined the effect of exercise</br>training on these parameters. Mitochondrial respiratory function was assessed, in mitochondria</br>freshly isolated from hindlimb muscles, using an Oroboros O2K respirometer with pyruvate +</br>malate as substrates, oligomycin as an ATP synthase inhibitor, and carbonyl cyanide 4-</br>(trifluoromethoxy) phenylhydrazone (FCCP) to establish maximal activity. A pre-training GXT</br>revealed profound exercise intolerance, which corresponded to reduced respiratory capacity,</br>citrate synthase (CS) and ETC complex 1 protein content of muscle mitochondria in the taz vs.</br>age-matched wild-type (WT) mice. Based on the pre-training GXT, exercise training was</br>conducted at 12-17 m/min, 0% grade for 60 min/d, 5d/wk, for 4 wks. Exercise training elicited a</br>99% increase in GXT run time in the taz mice ''P'' < 0.01 vs. pre-training), but failed to increase</br>times to those of sedentary WT mice. Training significantly decreased state 3 respiratory</br>capacity of muscle mitochondria from exercised mice (wild type sedentary (WTS): 4992.59 ±</br>371.35, wild type exercised (WTX): 3779.60 ± 561.43, taz sedentary (TazS): 2978.50 ± 383.53,</br>TazS: 1827.55 ± 525.17 (pmolO2/(s*mg), ''P'' = 0.02, Sed. vs. Ex.), and significantly decreased</br>mitochondrial 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).</br>Training also tended to reduce mitochondrial lactate dehydrogenase (LDH) and monocarboxylate</br>transporter 1 (MCT1) activities, MnSOD content, and 4-hydroxnonenal-protein adducts (index of</br>oxidative stress), but tended to increase mitochondrial UCP3 in exercised WT and taz mice.</br>Interestingly, training significantly increased muscle levels of CS (WTS: 1.491 ± 0.112, WTX:</br>1.792 ± 0.143, TazS: 1.325 ± 0.108, TazX: 1.550 ± 0.143 (RU/g),'' P'' = 0.05 Sed. v. Ex.),</br>suggesting increased muscle mitochondrial content with training. This study indicates that</br>exercise training improves functional capacity of taz deficient mice and induces selective</br>mitochondrial protein remodeling during mitochondrial biogenesis that perhaps mitigates</br>oxidative 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. </br></br>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. </br></br>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" (Taz^KD) 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 Taz^KD 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 Taz^KD 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 Taz^KD mitochondrial metabolism. Incubation of Taz^KD 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].</br></br>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. </br></br>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.</br></br>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.</br></br>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.</br></br>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.</br></br>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-x_L is an anti-a … Bcl-x_L 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 the</br>antioxidant and mitoprotective effect of a new promising neuroprotective molecule, JM-20, in mitochondria</br>and 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 glucoseinduced</br>H₂O₂ 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 reduction</br>peak 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 strategies</br>to combat ischemic brain damage.2+</sup> 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 + II_P : 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 F₁F_o-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'' F_o subunit into liposomes enhanced the ionophoric activity of BDQ. We discuss the possibility that localization of BDQ at F₁F_o-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;+</sup>/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.</br></br>© 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 increased</br>risk to develop type 2 diabetes and cardiovascular and metabolic diseases in adulthood.</br>The placental capacity to supply adequate amount of nutrients and oxygen to the fetus</br>represents one of the main determiner of the fetal growth. Despite its critical roles during</br>prenatal development, few studies have investigated the effects of maternal diet on the</br>placental physiology and functions. Our aim was to explore the placental adaptive proteomic</br>processes implicated in response to a maternal suboptimal nutrition.</br></br>Rat term placentas from 70% food-restricted</br>(FR30) mothers were used for a proteomic screen. Placental mitochondrial functions were</br>evaluated using molecular and functional approaches and ATP production was measured.</br>RESULTS – FR30 drastically reduced both placental and fetal weights. FR30 placentas</br>displayed 14 identified proteins differentially expressed, including several mitochondrial</br>proteins suggesting specific alterations of these organelles. FR30 induced a marked increase</br>of placental mtDNA content and changes in mitochondrial functions including modulation of</br>the expression of numerous genes implicated in both mitochondrial biogenesis and</br>bioenergetic pathways. Mitochondria under FR30 conditions showed higher oxygen</br>consumption but fail to maintain their critical ATP production.</br></br>We provide first evidence that maternal suboptimal nutrition induces</br>mitochondrial abnormalities in the placenta of growth-restricted fetuses. Although maternal</br>calorie restriction induces mitochondrial adaptive processes such as an increase of both</br>mitochondrial biogenesis and bioenergetic efficiency; placental ATP production was</br>drastically reduced. This disturbance may be implicated in reduction of the placental capacity</br>to actively transport nutrients that may strengthen the effect of maternal undernutrition on the</br>development of the fetus. Our data suggest that placental mitochondrial defects may be</br>implicated, 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.</br>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). </br>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. </br></br>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.</br></br>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.</br></br>© 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.)