Gnaiger 2020 BEC MitoPathways: Difference between revisions
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|abstract=[[File:BEC.png|25px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways]] [https://wiki.oroboros.at/images/e/ec/BEC_2020.2_doi10.26124bec2020-0002.pdf https://doi.org/10.26124/bec:2020-0002] | |abstract=[[File:BEC.png|25px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways]] [https://wiki.oroboros.at/images/e/ec/BEC_2020.2_doi10.26124bec2020-0002.pdf https://doi.org/10.26124/bec:2020-0002] |
Revision as of 21:56, 27 June 2022
Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5th ed. https://doi.org/10.26124/bec:2020-0002 |
» [[Has info::Bioenerg Commun 2020.2. Published online 2020-12-30
]]
Gnaiger Erich (BEC 2020.2) Bioenerg Commun
Abstract: [[has abstract:: https://doi.org/10.26124/bec:2020-0002
Did you know that keeping your mitochondria fit is essential for quality of life, brain and muscle function, and resistance against preventable, immunological, and age-related degenerative diseases?
The capacity of cellular oxidative phosphorylation (OXPHOS) — a direct measure of mitochondrial function — is a result of evolution, age, gender, lifestyle, and environment (EAGLE). Increasingly, western lifestyle and aging contribute to mitochondrial dysfunction and the current epidemic of preventable diseases, including neurodegenerative and cardiovascular diseases, obesity, diabetes, and various types of cancer. The mitObesity epidemic leads to multimorbidity in aging and threatens to overwhelm the capacity of healthcare systems.
Training in mitochondrial physiology and bioenergetics, therefore, has high relevance to society. The ‘Blue Book’ on Mitochondrial Pathways and Respiratory Control presents a fundamental introduction to OXPHOS analysis for students and researchers in life sciences ― from evolutionary biology to medical and environmental applications. It combines concepts of bioenergetics and biochemical pathways related to mitochondrial core energy metabolism, provides the basis for substrate-uncoupler-inhibitor titration (SUIT) protocols, and updates the terminology consistent with the MitoEAGLE white paper on Mitochondrial Physiology.
It is now our responsibility to transfer the enthusiasm for innovation, reproducibility, and quality in science, and to translate mitochondrial research into visionary healthcare solutions.
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• Keywords: [[has publicationkeywords::Q-junction]], [[has publicationkeywords::Respiratory states]], [[has publicationkeywords::Flux control ratios]], [[has publicationkeywords::Additivity]], [[has publicationkeywords::Body mass excess]]
• Bioblast editor: Gnaiger E
• O2k-Network Lab: AT Innsbruck Gnaiger E, AT Innsbruck Oroboros
A guide through the chapters
- Real-time OXPHOS analysis. — Richard Altmann’s bioblasts are the systematic unit of bioenergetics and chemiosmotic coupling studied in living cells and mitochondrial preparations. A rigorous understanding of mitochondrial respiratory control relies on a clear concept of metabolic states and rates, accurate measurement and normalization of oxygen flux, and analysis of mitochondrial pathways.
- Respiratory states and rates: coupling control. — A concept-driven terminology frames our perception of the meaning of respiratory states and rates, from ROUTINE respiration of living cells to the capacity of oxidative phosphorylation (OXPHOS) determined in mitochondrial preparations, electron transfer (ET) capacity, LEAK respiration, and the distinction of uncoupled, noncoupled, or dyscoupled respiration.
- Normalization of rate: flow, flux, and flux ratios. — ‘The challenges of measuring respiratory rate are matched by those of normalization’ (Gnaiger et al 2000). The effect of metabolic control variables on flow or flux can be expressed by normalization for rate in a reference state, and is evaluated relative to a background state. The concept of flux control efficiency is based on principles of thermodynamics and is guided by statistical considerations, to remove the bias of the classical respiratory control ratio.
- NADH-linked pathways through Complex CI: respiratory pathway control with pyruvate, glutamate, malate. — Substrate combinations feeding electrons into the ET system through NADH have been considered to reflect physiological respiratory states in mitochondrial preparations. These protocols ignored the importance of cataplerotic metabolite depletion in the tricarboxylic acid (TCA) cycle.
- S-pathway through Complex CII, F-pathway through CETF, Gp-pathway through CGpDH. — Succinate as the substrate of CII is at a level comparable to NADH as the substrate for CI. Too many textbooks and publications propagate the error of comparing NADH in the N-pathway with FADH2 in the S-pathway ― together with fumarate, FADH2 is a product but not a substrate of CII.
- NS-pathway through Complexes CI & CII: convergent electron transfer at the Q-junction. — The term ‘electron transport chain’ is a misnomer in bioenergetics, conceiling the convergent pathway architecture of the electron transfer system (ETS). This has direct implications on the design of substrate-uncoupler-inhibitor titration (SUIT) protocols, for reconstitution of TCA cycle function, and sequential separation of branches of mitochondrial pathways for OXPHOS analysis.
- Additivity of convergent electron transfer. — OXPHOS capacity depends on the degree of additivity of pathways converging at the Q-junction. Paradoxically, current concepts on interaction do not agree whether to categorize incompletely additive effects as synergistic or antagonistic. A new mathematical definition of additivity bridges the gap between these apparently incompatible models of interaction.
- Protonmotive pressure and respiratory control. — Why is thermodynamics scary? The driving force of chemical reactions is confusingly called an energy (Gibbs energy), whereas it is actually an isomorphic force, linked to the electric and chemical terms of the protonmotive force. The gas law represents chemical force and gas pressure. Flux-force relations are non-linear. Why should we consider Fick’s linear law of diffusion and protonmotive pressure in the control of flux?
Preface
- Mitochondrial physiology is part of our lives. Mitochondrial fitness — the capacity of oxidative phosphorylation (OXPHOS) — is essential for the quality of your life, for brain and muscle function, for resistance against preventable and age-related degenerative diseases. Evolutionary background, age, gender (sex), lifestyle, and environmental factors (EAGLE) determine mitochondrial fitness, which is OXPHOS capacity and multiple mitochondrial functions. Comprehensive OXPHOS analysis is vital for understanding your cells, vital for our health care systems, and vitally deserves reliability and reproducibility of analytical and diagnostic studies.
- The Blue Book on Mitochondrial Pathways and Respiratory Control presents a fundamental introduction to OXPHOS analysis. It combines concepts of bioenergetics and biochemical pathways related to mitochondrial (mt) core energy metabolism and provides the basis for the substrate-uncoupler-inhibitor titration (SUIT) protocols in high-resolution respirometry, which have been established since publication of the first edition of MitoPathways in 2007 (Fig. 1).
- Application of SUIT protocols for real-time OXPHOS analysis is a component of metabolic phenotyping (Fig. 2). OXPHOS analysis extends conventional bioenergetics to the level of mitochondrial physiology for functional diagnosis in health and disease. The Oroboros O2k for HRR has the high signal stability and unrestricted flexibility of titrations suited for application of elementary and complex SUIT protocols.
- Since 2007, research in mitochondrial physiology sparked a revolution of bioenergetics by experimental design that appreciates the convergent architecture of the electron transfer system (ETS) with multiple branches of mitochondrial pathways converging at the Q-junction, leading to a novel concept of additivity introduced in the new Chapter 7 of the Blue Book. These advancements are documented by >1 000 reports listed under 'NS-pathway control state' in MitoPedia. To study respiratory control at the Q-junction, SUIT protocols are applied with physiological substrate cocktails, particularly NADH-linked substrates (N) in combination with succinate (NS), fatty acids (FNS), and glycerophosphate (FNSGp), which have been introduced for the first time in the 1st edition of MitoPathways (2007).
- Since then, ‘MitoPedia’ was initiated and the COST Action MitoEAGLE flies. 666 coauthors joined forces to present a harmonized nomenclature on Mitochondrial Physiology (Bioenerg Commun 2020.1), with an emphasis on conceptual consistency for establishing a quality-controlled database on mitochondrial respiratory physiology. The 5th edition of MitoPathways gained from this collaboration. Many terms and symbols are simplified or presented in a more explicit form compared to the 2014 edition. Terms and iconic symbols develop meaning in context. Contextual meaning is best communicated by stories told in entertaining lectures, or by equations even if they turn off the most motivated student. Motivation is never enough. We need passion, persistence, resilience to transpose equations, terms and stories into the domain of personal experience, gaining perspective from perception to conception. The best scientific experience is the experiment driven by a hypothetical story written in clear words and forged into meaningful equations. This may provide a guideline to the critical discussion of the ergodynamic concept of the protonmotive force and chemiosmotic pressure, inspired by the Grey Book of Peter Mitchell and added as the new Chapter 8 of the Blue Book.
- Mitochondria are the structural and functional elementary units of cell respiration. MitoPathways is an element of the Oroboros Ecosystem driven by high-resolution respirometry and shaping mitochondrial physiology. A mosaic evolves by combining the elements into a picture of modern mitochondrial respiratory physiology.
- I thank all collaborators of the NextGen-O2k project and the authors and coauthors of various publications emerging from international cooperations, particularly the Horizon 2020 funded COST Action CA15203 MitoEAGLE. Without the team at Oroboros Instruments, including our partners in electromechanical engineering (O2k; WGT-Elektronik, Kolsass, Austria) and DatLab software development the experimental advances on MitoPathways would not have been possible.
- Erich Gnaiger
- Innsbruck, 2007 - 2020
Acknowledgements
- Specific thanks is extended to Oroboros team members Luiza Cardoso, Cristiane Cecatto, Carolina Doerrier, Sabine Schmitt, Timea Komlódi, Zulfiya Orynbayeva, and Lucie Zdrazilova for critical reading and helpful suggestions on various chapters, and to Univ.-Prof. Dr. Markus Haltmeier (Applied Mathematics, Univ Innsbruck, Austria) for stimulating discussions on additivity (Chapter 7).
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Chapters: References and notes
- References Preface
- Gnaiger E (2014) Mitochondrial pathways and respiratory control. 4th ed. Oroboros MiPNet Publications, Innsbruck:80 pp. - »Bioblast link«
- Gnaiger E ed (2007) Mitochondrial pathways and respiratory control. 1st ed. Oroboros MiPNet Publications, Innsbruck:96 pp. - »Bioblast link«
- Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. doi:10.26124/bec:2020-0001.v1.
- References Preface
Chapter 1. Real-time OXPHOS analysis
References: 1. OXPHOS
- Altmann R (1894) Die Elementarorganismen und ihre Beziehungen zu den Zellen. Zweite vermehrte Auflage. Verlag Von Veit & Comp, Leipzig:160 pp, 34 Tafeln. - »Bioblast link«
- Dawson KD, Baker DJ, Greenhaff PL, Gibala MJ (2005) An accute decrease in TCA cycle intermediates does not affect aerobic energy delivery in contracting rat skeletal muscle. - »Bioblast link«
- Garlid KD, Semrad C, Zinchenko V (1993) Does redox slip contribute significantly to mitochondrial respiration? - »Bioblast link«
- Gibala MJ, MacLean DA, Graham TE, Saltin B (1998) Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise. - »Bioblast link« - Concentrations of TCA cycle intermediates.
- Gnaiger E (1983) Heat dissipation and energetic efficiency in animal anoxibiosis. Economy contra power. - »Bioblast link«
- Gnaiger E (1993) Efficiency and power strategies under hypoxia. Is low efficiency at high glycolytic ATP production a paradox? - »Bioblast link« - The Gibbs force of phorphorylation of ADP to ATP is FATP = 52 to 66 kJ/mol ATP under intracellular conditions.
- Gnaiger E (1993) Nonequilibrium thermodynamics of energy transformations. - »Bioblast link«
- Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. - »Bioblast link«
- Gnaiger E (2008) Polarographic oxygen sensors, the oxygraph and high-resolution respirometry to assess mitochondrial function. - »Bioblast link«
- Gnaiger Erich (2020) Canonical reviewer's comments on: Bureau International des Poids et Mesures (2019) The International System of Units (SI) 9th ed. https://doi.org/doi:10.26124/mitofit:200004. -
- Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. https://doi.org/10.26124/bec:2020-0001.v1. - »Bioblast link«
- Gnaiger E, Kuznetsov AV (2002) Mitochondrial respiration at low levels of oxygen and cytochrome c. - »Bioblast link«
- Gnaiger E, Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Steurer W, Margreiter R (2000b) Mitochondria in the cold. - »Bioblast link« – MiR05 as the basis of MiR06.
- Gnaiger E, Lassnig B, Kuznetsov AV, Margreiter R (1998) Mitochondrial respiration in the low oxygen environment of the cell: Effect of ADP on oxygen kinetics. - »Bioblast link«
- Gnaiger E, Lassnig B, Kuznetsov AV, Rieger G, Margreiter R (1998) Mitochondrial oxygen affinity, respiratory flux control, and excess capacity of cytochrome c oxidase. - »Bioblast link«
- Gueguen N, Lefaucheur L, Ecolan P, Fillaut M, Herpin P (2005) Ca2+-activated myosin-ATPases, creatine and adenylate kinases regulate mitochondrial function according to myofibre type in rabbit. - »Bioblast link«
- Hatefi Y, Haavik AG, Fowler LR, Griffiths DE (1962) Studies on the electron transfer-pathway. XLII. Reconstitution of the electron transfer-pathway. - »Bioblast link«
- Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Mark W, Steurer W, Saks V, Usson Y, Margreiter R, Gnaiger E (2004) Mitochondrial defects and heterogeneous cytochrome c release after cardiac cold ischemia and reperfusion. - »Bioblast link« – Cytochrome c test.
- Lane N (2005) Power, sex, suicide: Mitochondria and the meaning of life. - »Bioblast link«
- Lemieux H, Blier PU, Gnaiger E (2017) Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers. https://doi.org/10.1038/s41598-017-02789-8 - »Bioblast link«
- Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. - »Bioblast link«
- Mitchell P (1966) Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Glynn Research Ltd, Bodmin:192 pp. - »Bioblast link« - The Grey Book 1. - "or, writing Δp for the P.M.F." (p. 35)
- Mitchell P (1968) Chemiosmotic coupling and energy transduction. Glynn Research Ltd, Bodmin:111 pp. - The Grey Book 2.
- Mitchell P, Moyle J (1967) Respiration-driven proton translocation in rat liver mitochondria. Biochem J 105:1147-62. - »Bioblast link«
- Mootha VK, Arai AE, Balaban RS (1997) Maximum oxidative phosphorylation capacity of the mammalian heart. - »Bioblast link« – [Pi] <10 mM and [ADP] <0.4 mM limit OXPHOS in isolated heart mitochondria.
- Nicholson JK, Holmes E, Kinross JM, Darzi AW, Takats Z, Lindon JC (2012) Metabolic phenotyping in clinical and surgical environments. - »Bioblast link«
- Owen OE, Kalhan SC, Hanson RW (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. - »Bioblast link«
- Pesta D, Gnaiger E (2012) High-resolution respirometry. OXPHOS protocols for human cells and permeabilized fibres from small biopisies of human muscle. - »Bioblast link« - >90 % saturation is reached only >5 mM ADP, yet previously few studies used such high [ADP] in permeabilized tissues and cells. - Oxygen limitation of respiration below air saturation.
- Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria – case studies. - »Bioblast link« - Cytochrome c test.
- Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. - »Bioblast link« - Cytochrome c test.
- Renner K , Amberger A, Konwalinka G, Gnaiger E (2003) Changes of mitochondrial respiration, mitochondrial content and cell size after induction of apoptosis in leukemia cells. - »Bioblast link« -
- Rossignol R, Faustin B, Rocher C, Malgat M, Mazat JP, Letellier T (2003) Mitochondrial threshold effects. - »Bioblast link«
- Saks VA, Veksler VI, Kuznetsov AV, Kay L, Sikk P, Tiivel T, Tranqui L, Olivares J, Winkler K, Wiedemann F, Kunz WS (1998) Permeabilised cell and skinned fiber techniques in studies of mitochondrial function in vivo. - »Bioblast link« - The apparent Km for ADP increases up to 0.5 mM in some permeabilized muscle fibres.
- Territo PR, Mootha VK, French SA, Balaban RS (2000) Ca2+ activation of heart mitochondrial oxidative phosphorylation: role of the FO/F1-ATPase. - »Bioblast link«
Notes: OXPHOS
Chapter 2. Respiratory states and rates: coupling control
References: 2. States and rates
- Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. - »Bioblast link«
- Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. - »Bioblast link«
- Chance B, Williams GR (1956) The respiratory chain and oxidative phosphorylation. - »Bioblast link«
- Estabrook R (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. - »Bioblast link«
- Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. - »Bioblast link«
- Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. https://doi.org/10.26124/bec:2020-0001.v1. - »Bioblast link«
- Gnaiger E, Lassnig B, Kuznetsov AV, Margreiter R (1998) Mitochondrial respiration in the low oxygen environment of the cell: Effect of ADP on oxygen kinetics. - »Bioblast link« - Oxygen kinetics is different in the LEAK state without adenylates (LN) and State 4 (LEAK state with ATP, LN).
- Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. - »Bioblast link«
- König T, Nicholls DG, Garland PB (1969) The inhibition of pyruvate and Ls(+)-isocitrate oxidation by succinate oxidation in rat liver mitochondria. - »Bioblast link« - 3½ has been suggested to indicate an intermediate mitochondrial energy state somewhere between States 3 and 4. Would, therefore, State 4 be considered as being somewhere between State 3 and 5?
- Krumschnabel G, Eigentler A, Fasching M, Gnaiger E (2014) Use of safranin for the assessment of mitochondrial membrane potential by high-resolution respirometry and fluorometry. - »Bioblast link«
- Singh Simon (1997) Fermat's last theorem. Fourth Estate, London 340 pp. - »Bioblast link«
Notes: Coupling states
-
- A colour code is used with red and green in analogy to the states at a traffic light: at red, the motor is running in neutral gear (uncoupled) at minimum turnover without output (producing some heat) just to keep the engine running; at green, the motor is switched into gear and driven in a coupled state with full output. The blue colour is used to indicate a state of maximum input in neutral gear, or pressing fully the accelerator and the clutch simultaneously, which yields maximum turnover without output and produces a maximum of heat. The analogy for coupling in OXPHOS and in cars has its limitations but may help to memories the red/green colour code - you may think of it when your car is in a LEAK at the next red traffic light.
- H+ translocation through pumps is shown by dotted arrows across the mtIM.
-
Chapter 3. Normalization of rate: flow, flux, and flux ratios
References: 3. Normalization
- Aguirre E, Rodríguez-Juárez F, Bellelli A, Gnaiger E, Cadenas S (2010) Kinetic model of the inhibition of respiration by endogenous nitric oxide in intact cells. - »Bioblast link« - Tables 3.1 and 3.2: HEK 293
- Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. - »Bioblast link«
- Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. - »Bioblast link«
- Doerrier C, Garcia-Souza LF, Krumschnabel G, Wohlfarter Y, Mészáros AT, Gnaiger E (2018) High-Resolution FluoRespirometry and OXPHOS protocols for human cells, permeabilized fibers from small biopsies of muscle, and isolated mitochondria. - »Bioblast link«
- Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. - »Bioblast link«
- Hütter E, Renner K, Pfister G, Stöckl P, Jansen-Dürr P, Gnaiger E (2004) Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts. - »Bioblast link« - Tables 3.1 and 3.2: fibrolasts; Figure 3.1.
- Hütter E, Unterluggauer H, Garedew A, Jansen-Dürr P, Gnaiger E (2006) High-resolution respirometry - a modern tool in aging research. - »Bioblast link«
- Renner K, Amberger A, Konwalinka G, Gnaiger E (2003) Changes of mitochondrial respiration, mitochondrial content and cell size after induction of apoptosis in leukemia cells. - »Bioblast link« - Tables 3.1 and 3.2: CEM
- Stadlmann S, Renner K, Pollheimer J, Moser PL, Zeimet AG, Offner FA, Gnaiger E (2006) Preserved coupling of oxidative phosphorylation but decreased mitochondrial respiratory capacity in IL-1ß treated human peritoneal mesothelial cells. - »Bioblast link«
4-compartmental OXPHOS model. (1) ET capacity E of the noncoupled electron transfer system ETS. OXPHOS capacity P is partitioned into (2) the dissipative LEAK component L, and (3) ADP-stimulated P-L net OXPHOS capacity. (4) If P-L is kinetically limited by a low capacity of the phosphorylation system to utilize the protonmotive force pmF, then the apparent E-P excess capacity is available to drive coupled processes other than phosphorylation P» (ADP to ATP) without competing with P».
- Bioblast links: Coupling control - >>>>>>> - Click on [Expand] or [Collapse] - >>>>>>>
1. Mitochondrial and cellular respiratory rates in coupling-control states
Respiratory rate | Defining relations | Icon | |
---|---|---|---|
OXPHOS capacity | P = P´-Rox | ![]() |
mt-preparations |
ROUTINE respiration | R = R´-Rox | ![]() |
living cells |
ET capacity | E = E´-Rox | ![]() |
» Level flow |
» Noncoupled respiration - Uncoupler | |||
LEAK respiration | L = L´-Rox | ![]() |
» Static head |
» LEAK state with ATP | |||
» LEAK state with oligomycin | |||
» LEAK state without adenylates | |||
Residual oxygen consumption Rox | L = L´-Rox | ![]() |
2. Flux control ratios related to coupling in mt-preparations and living cells
FCR | Definition | Icon | |
---|---|---|---|
L/P coupling-control ratio | L/P | ![]() |
» Respiratory acceptor control ratio, RCR = P/L |
L/R coupling-control ratio | L/R | ![]() | |
L/E coupling-control ratio | L/E | ![]() |
» Uncoupling-control ratio, UCR = E/L (ambiguous) |
P/E control ratio | P/E | ![]() | |
R/E control ratio | R/E | ![]() |
» Uncoupling-control ratio, UCR = E/L |
net P/E control ratio | (P-L)/E | ![]() | |
net R/E control ratio | (R-L)/E | ![]() |
3. Net, excess, and reserve capacities of respiration
Respiratory net rate | Definition | Icon |
---|---|---|
P-L net OXPHOS capacity | P-L | ![]() |
R-L net ROUTINE capacity | R-L | ![]() |
E-L net ET capacity | E-L | ![]() |
E-P excess capacity | E-P | ![]() |
E-R reserve capacity | E-R | ![]() |
4. Flux control efficiencies related to coupling-control ratios
Coupling-control efficiency | Definition | Icon | Canonical term | ||
---|---|---|---|---|---|
P-L control efficiency | jP-L | = (P-L)/P | = 1-L/P | ![]() |
P-L OXPHOS-flux control efficiency |
R-L control efficiency | jR-L | = (R-L)/R | = 1-L/R | ![]() |
R-L ROUTINE-flux control efficiency |
E-L coupling efficiency | jE-L | = (E-L)/E | = 1-L/E | ![]() |
E-L ET-coupling efficiency » Biochemical coupling efficiency |
E-P control efficiency | jE-P | = (E-P)/E | = 1-P/E | ![]() |
E-P ET-excess flux control efficiency |
E-R control efficiency | jE-R | = (E-R)/E | = 1-R/E | ![]() |
E-R ET-reserve flux control efficiency |
5. General
- » Basal respiration
- » Cell ergometry
- » Dyscoupled respiration
- » Dyscoupling
- » Electron leak
- » Electron-transfer-pathway state
- » Hyphenation
- » Oxidative phosphorylation
- » Oxygen flow
- » Oxygen flux
- » Permeabilized cells
- » Phosphorylation system
- » Proton leak
- » Proton slip
- » Respiratory state
- » Uncoupling
Chapter 4. NADH-linked pathways through Complex I: respiratory pathway control with pruvate, glutamate, malate
References: 4. N-pathways
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- Brewer GJ, Jones TT, Wallimann T, Schlattner U (2004) Higher respiratory rates and improved creatine stimulation in brain mitochondria isolated with antioxidants. - »Bioblast link«
- Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. - »Bioblast link« - Substrate depletion in isolated mitochondria is achieved in State 2: ADP is added to induce a transient stimulation of oxygen flux based on oxidation of endogenous substrates.
- Digerness SB, Reddy WJ (1976) The malate-aspartate shuttle in heart mitochondria. J Mol Cell Cardiol. 8:779-85.
- Duchen MR (2004) Roles of mitochondria in health and disease. Diabetes 53, Suppl 1:S96-102. - Mitochondrial glutamate dehydrogenase is particularly active in astrocytes, preventing glutamate induced neurotoxicity.
- Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. - »Bioblast link«
- Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. - »Bioblast link« - Equilibrium ratio of malate to fumarate is 4.1.
- Hildyard JCW, Halestrap AP (2003) Identification of the mitochondrial pyruvate carrier in Saccharomyces cerevidiae. Biochem J 374:607-11.
- Johnson G, Roussel D, Dumas JF, Douay O, Malthiery Y, Simard G, Ritz P (2006) Influence of intensity of food restriction on skeletal muscle mitochondrial energy metabolism in rats. Am J Physiol Endocrinol Metab 291:E460-7. - Uncoupling stimulates coupled OXPHOS respiration, PMP, by 14 %.
- Kemp RB, Hoare S, Schmalfeldt M, Bridge CM, Evans PM, Gnaiger E (1994) A thermochemical study of the production of lactate by glutaminolysis and glycolysis in mouse macrophage hybridoma cells. - »Bioblast link« - Glutamate derived from hydrolyzation of glutamine is a very important aerobic substrate in cultured cells.
- Lemasters JJ (1984) The ATP-to-oxygen stoichiometries of oxidative phosphorylation by rat liver mitochondria. - »Bioblast link« - Malonate added to inhibit the succinate-fumarate reaction exerts only a minor effect on liver mitochondrial respiration.
- Maechler P, Carobbio S, Rubi B (2006) In beta-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion. Int J Biochem Cell Biol 38:696-709.
- Messer JI, Jackman MR, Willis WT (2004) Pyruvate and citric acid cycle carbon requirements in isolated skeletal muscle mitochondria. - »Bioblast link« - With malate alone and saturating [ADP] isolated rat skeletal muscle mitochondria respire at only 1.3 % of OXPHOS capacity with pyruvate+malate. Pyruvate alone yields only 2.1 % of OXPHOS capacity (P) with PM.
- Nicholls DG, Ferguson SJ (2002) Bioenergetics 3. - »Bioblast link« - Carriers.
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- Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. - »Bioblast link« - Uncoupling stimulates coupled OXPHOS respiration, PMP, by 15 % in human skeletal muscle. OXPHOS with glutamate alone is 50 % to 85 % of respiration with glutamate&malate. - OXPHOS with glutamate&malate is identical or 10 % higher than with pyruvate&malate.
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Notes: N-pathways
- N-pathway control state
- The metabolic maps in this and the following chapters have been modified and extended in comparison to previous editions. Added substrates are printed in blue in contrast to intermediates printed in black. CI-linked substrates and intermediates are shown with white background, whereas added succinate and consecutively formed fumarate are distinguished with a yellow background (FADH2 and the corresponding arrows are emphasized by yellow shades). Intermediates with grey background are considered to be present at low concentrations due to metabolite depletion, whereas products with blue background are considered to accumulate in the matrix space or in equilibrium with the large volume of incubation medium or to increase in equilibrium with the supplied substrate.
- Schwerzmann et al (1989) Proc Natl Acad Sci U S A 86:1583-7. - “Of the substrates used here, pyruvate/malate activates the chain at complex I, glutamate/malate and succinate at complexes II and III, ..” - This consideration of glutamate&malate requires correction.
- Ponsot et al (2005) J Cell Physiol 203:479-86. - (a) Respiration (State 3) in permeabilized fibres with malate alone gave 25-50 % of the flux with pyruvate+malate. This needs to be discussed in terms of endogenous mitochondrial substrates, which interfere to an unknown degree with the kinetics of respiration after addition of exogenous substrates, or the activity of malic enzyme. (b) Maximal respiration rates in muscle should be evaluated at saturating or high Pi, since at a Pi concentration of 3 mM OXPHOS respiration may be phosphate limited.
- Hulbert et al (2006) J Comp Physiol B 176:93-105. Addition of ‘sparking malate concentrations’. This term can probably be derived from the misconception that tricarboxylic acid cycle intermediates are conserved during respiration of isolated mitochondria. 380 µM malate in conjunction with 2.4 mM pyruvate were used, which makes a comparison difficult between different tissues and different species: the low substrate concentrations may limit PMP flux at various degrees in the different sources of mitochondria, and GMP or PGMP may support higher fluxes than PMP at tissue- and species-specific degrees.
Chapter 5. S-pathway through Complex II, F-pathway through electron-transferring flavoprotein, Gp-pathway through glycerophosphate dehydrogenase
References: 5. S-, F-, Gp-pathways
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Notes: S-, F-, Gp-pathways
- Succinate pathway
- Ponsot et al (2005) J Cell Physiol 203:479-86. - ‘.. the mitochondrial form of GPDH, which produces FADH2 within the mitochondrial matrix and provides electrons to Compoex II of the phosphorylation chain’. – The mitochondrial glycerophosphate dehydrogenase complex (CGpDH), located on the outer side of the inner mitochondrial membrane, does not provide electrons to CII, but feeds electrons into the Q-cycle entirely independent of CII. FADH2 is not produced within the mitochondrial matrix. Electron transfer takes place from the mitochondrial inner membrane flavoprotein-linked glycerophosphate dehydrogenase complex to CoQ.
Chapter 6. NS-pathway through Complexes CI & CII: convergent electron transfer at the Q-junction and additive effect of substrate combinations
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Notes: Q-junction
- NS-pathway control state
- Identical GMP/GSP or GMP/GMSP ratios of 0.7 are reported for isolated mitochondria (Rasmussen and Rasmussen 2000; Capel et al 2005) and permeabilized fibres (Kunz et al 2000). For a review see Gnaiger (2009).
Chapter 7. Additivity of convergent electron transfer
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Chapter 8. Protonmotive pressure and respiratory control
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A. Conversions of metabolic fluxes
References: A. Conversions
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B: SUIT
B1. Substrates, uncouplers and inhibitors
Abbreviations
- ADP - adenosine diphosphate
- ATP - adenosine triphosphate
- BMR - basal metabolic rate
- ce - living cells
- CHNO - reduced fuel substrate
- cO2 [µM] - O2 concentration
- dce - dead cells
- E - ET capacity
- ET - electron transfer
- ETS - electron transfer system
- IO2 - oxygen flow
- jcyt c - cytochrome c control efficiency; jcyt c = (JCHNOc-JCHNO)/JCHNOc
- JO2 - oxygen flux
- jE-L=(E-L)/E - ET-coupling efficiency
- JV,O2 - volume-specific O2 flux, per V of the experimental chamber
- J°O2 - instrumental background O2 flux
- k - catabolic reaction
- L - LEAK rate of respiration
- M - malate
- MiR05 - mitochondiral respiration medium 5
- Nce [x] - cell count
- N-pathway - NADH-linked pathway
- NS-pathway - convergent NADH- and succinate-linked pathway
- OXPHOS - oxidative phosphorylation
- P - pyruvate
- P - OXPHOS capacity
- Pi - inorganic phosphate
- pO2 [kPa] - partial oxygen pressure
- R - ROUTINE respiration
- Rox - residual oxygen consumption
- rO2 - rate of concentration change
- S - succinate
- SO2 [µmol·kPa-1] - oxygen solubility
- S-pathway - succinate-linked pathway
- t [s] - time
- V [L] - volume of the experimental chamber
- vce - viable cells
- νO2 - stoichiometric number of O2 in a specified transformation, such as the reaction k
- ξ - advancement of a transformation
Cited by
- Gnaiger E (2021) Beyond counting papers – a mission and vision for scientific publication. Bioenerg Commun 2021.5. https://doi:10.26124/BEC:2021-0005
- Gnaiger E (2021) Bioenergetic cluster analysis – mitochondrial respiratory control in human fibroblasts. MitoFit Preprints 2021.8. https://doi.org/10.26124/mitofit:2021-0008
- Krako Jakovljevic N, Ebanks B, Katyal G, Chakrabarti L, Markovic I, Moisoi N (2021) Mitochondrial homeostasis in cellular models of Parkinson’s Disease. Bioenerg Commun 2021.2. https://doi.org/10.26124/bec:2021-0002
- Komlódi T, Cardoso LHD, Doerrier C, Moore AL, Rich PR, Gnaiger E (2021) Coupling and pathway control of coenzyme Q redox state and respiration in isolated mitochondria. Bioenerg Commun 2021.3. https://doi.org/10.26124/bec:2021-0003
- Cardoso et al (2021) Magnesium Green for fluorometric measurement of ATP production does not interfere with mitochondrial respiration. Bioenerg Commun 2021.1. doi:10.26124/bec:2021-0001
- Went N, Di Marcello M, Gnaiger E (2021) Oxygen dependence of photosynthesis and light-enhanced dark respiration studied by High-Resolution PhotoRespirometry. MitoFit Prep 2021.5. - »Bioblast link«
- Silva et al (2021) Off-target effect of etomoxir on mitochondrial Complex I. MitoFit Preprints 2021. (in preparation)
- Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. doi:10.26124/bec:2020-0001.v1.
- Gnaiger E (2021) Bioenergetic cluster analysis – mitochondrial respiratory control in human fibroblasts. MitoFit Preprints 2021.8. https://doi.org/10.26124/mitofit:2021-0008
- Komlódi et al (2022) The protonmotive force - not merely membrane potential. MitoFit Preprints 2022 (in prep)
- Komlódi et al (2022) The protonmotive force - not merely membrane potential. MitoFit Preprints 2022 (in prep)
Labels: MiParea: Respiration, Instruments;methods, mt-Biogenesis;mt-density, Comparative MiP;environmental MiP, Exercise physiology;nutrition;life style, mt-Medicine, mt-Awareness
Organism: Human, Mouse
Tissue;cell: Heart, Skeletal muscle, Fibroblast
Preparation: Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, Intact cells
Regulation: Coupling efficiency;uncoupling, Flux control, mt-Membrane potential, Threshold;excess capacity, Uncoupler Coupling state: LEAK, ROUTINE, OXPHOS, ET Pathway: F, N, S, Gp, CIV, NS, ROX HRR: Oxygraph-2k, O2k-Fluorometer, O2k-Protocol, Theory
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