Gnaiger 2020 BEC MitoPathways

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CA15203 MitoEAGLE


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Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5th ed. Bioenerg Commun 2020.2: 112 pp. doi:10.26124/bec:2020-0002

» Bioblast pdfPublished online: 2020-Dec-30

Gnaiger Erich (2020) Bioenerg Commun

Abstract: Version 1 (v1) 2020-12-30 doi: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.

Keywords: Q-junction, Respiratory states, Flux control ratios, Additivity, Body mass excess Bioblast editor: Gnaiger E O2k-Network Lab: AT Innsbruck Gnaiger E, AT Innsbruck Oroboros

ORCID: ORCID.png Gnaiger Erich

The Blue Book

MitoPathways Supplement s1: Poster

Contents


Gnaiger 2020 BEC MitoPathways

A guide through the chapters


  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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?
Gnaiger 2020 BEC MitoPathways

Preface

Blue book banner.jpg
Figure 1. The Blue Book: Mitochondrial Pathways and Respiratory Control 1st edition (2007). 1st Mitochondrial Physiology Summer School, MiPsummer July 2007, Schröcken, Austria.
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).
Fig. 2.
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).
Gnaiger 2020 BEC MitoPathways

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Gnaiger 2020 BEC MitoPathways

Chapters: References and notes

References Preface
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» MitoPedia: Terms and abbreviations
Gnaiger 2020 BEC MitoPathways
Fig. 1.1.

Chapter 1. Real-time OXPHOS analysis

Fig. 1.2.

References: 1. OXPHOS

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  6. Gnaiger E (1993) Efficiency and power strategies under hypoxia. Is low efficiency at high glycolytic ATP production a paradox? In: Surviving Hypoxia: Mechanisms of Control and Adaptation. Hochachka PW, Lutz PL, Sick T, Rosenthal M, Van den Thillart G (eds) CRC Press, Boca Raton, Ann Arbor, London, Tokyo:77-109. - »Bioblast link« - The Gibbs force of phorphorylation of ADP to ATP is FATP = 52 to 66 kJ/mol ATP under intracellular conditions.
  7. Gnaiger E (1993) Nonequilibrium thermodynamics of energy transformations. Pure Appl Chem 65:1983-2002. - »Bioblast link«
  8. Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. Adv Exp Med Biol 543:39-55. - »Bioblast link«
  9. Gnaiger E (2008) Polarographic oxygen sensors, the oxygraph and high-resolution respirometry to assess mitochondrial function. In: Mitochondrial Dysfunction in Drug-Induced Toxicity (Dykens JA, Will Y, eds) John Wiley & Sons, Inc, Hoboken, NJ:327-52. - »Bioblast link«
  10. Gnaiger Erich (2020) Canonical reviewer's comments on: Bureau International des Poids et Mesures (2019) The International System of Units (SI) 9th ed. MitoFit Preprint Arch 2020.4 doi:10.26124/mitofit:200004. -
    Fig. 1.4.
    Fig. 1.5.
  11. Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. doi:10.26124/bec:2020-0001.v1. - »Bioblast link«
  12. Gnaiger E, Kuznetsov AV (2002) Mitochondrial respiration at low levels of oxygen and cytochrome c. Biochem Soc Trans 30:252-8. - »Bioblast link«
  13. Gnaiger E, Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Steurer W, Margreiter R (2000b) Mitochondria in the cold. In: Life in the cold. (Heldmaier G, Klingenspor M, eds) Springer, Heidelberg, Berlin, New York:431-42. - »Bioblast link« – MiR05 as the basis of MiR06.
  14. 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. Biochim Biophys Acta 1365:249-54. - »Bioblast link«
  15. Gnaiger E, Lassnig B, Kuznetsov AV, Rieger G, Margreiter R (1998) Mitochondrial oxygen affinity, respiratory flux control, and excess capacity of cytochrome c oxidase. J Exp Biol 201:1129-39. - »Bioblast link«
  16. 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. J Physiol 564:723-35. - »Bioblast link«
  17. Hatefi Y, Haavik AG, Fowler LR, Griffiths DE (1962) Studies on the electron transfer-pathway. XLII. Reconstitution of the electron transfer-pathway. J Biol Chem 237:2661-9. - »Bioblast link«
  18. 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. Am J Physiol Heart Circ Physiol 286:H1633–41. - »Bioblast link« – Cytochrome ‘’c’’ test.
  19. Lane N (2005) Power, sex, suicide: Mitochondria and the meaning of life. Oxford University Press. 354 pp. - »Bioblast link«
  20. 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. Sci Rep 7:2840, DOI:10.1038/s41598-017-02789-8. - »Bioblast link«
  21. Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191:144-8. - »Bioblast link«
  22. 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)
  23. Mitchell P (1968) Chemiosmotic coupling and energy transduction. Glynn Research Ltd, Bodmin:111 pp. - The Grey Book 2.
  24. Mitchell P, Moyle J (1967) Respiration-driven proton translocation in rat liver mitochondria. Biochem J 105:1147-62. - »Bioblast link«
  25. Mootha VK, Arai AE, Balaban RS (1997) Maximum oxidative phosphorylation capacity of the mammalian heart. Am J Physiol 272:H769-75. - »Bioblast link« – [Pi] <10 mM and [ADP] <0.4 mM limit OXPHOS in isolated heart mitochondria.
  26. Nicholson JK, Holmes E, Kinross JM, Darzi AW, Takats Z, Lindon JC (2012) Metabolic phenotyping in clinical and surgical environments. Nature 491:384-92. - »Bioblast link«
  27. Owen OE, Kalhan SC, Hanson RW (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 277:30409-12. - »Bioblast link«
  28. Pesta D, Gnaiger E (2012) High-resolution respirometry. OXPHOS protocols for human cells and permeabilized fibres from small biopisies of human muscle. Methods Mol Biol 810:25-58. - »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.
  29. 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. Mitochondrion 4:377-85. - »Bioblast link« - Cytochrome c test.
  30. Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. Mol Cell Biochem 208:37-44. - »Bioblast link« - Cytochrome c test.
  31. 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. Biochim Biophys Acta 1642:115-23. - »Bioblast link« -
    Fig.1.6A.
  32. Rossignol R, Faustin B, Rocher C, Malgat M, Mazat JP, Letellier T (2003) Mitochondrial threshold effects. Biochem J 370:751-62. - »Bioblast link«
  33. 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. Mol Cell Biochem 184:81-100. - »Bioblast link« - The apparent Km for ADP increases up to 0.5 mM in some permeabilized muscle fibres.
  34. Territo PR, Mootha VK, French SA, Balaban RS (2000) Ca2+ activation of heart mitochondrial oxidative phosphorylation: role of the F0/F1-ATPase. Am J Physiol Cell Physiol 278:C423-35. - »Bioblast link«

Notes: OXPHOS

  1. Mitochondrial markers
Gnaiger 2020 BEC MitoPathways
States 1-2-3-4-5.jpg
RCR and OXPHOS coupling eff.jpg

Chapter 2. Respiratory states and rates: coupling control

References: 2. States and rates

  1. Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. J Biol Chem 217:383-93. - »Bioblast link«
  2. Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem 217:409-27. - »Bioblast link«
  3. Chance B, Williams GR (1956) The respiratory chain and oxidative phosphorylation. Adv Enzymol17:65-134. - »Bioblast link«
  4. Estabrook R (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. Meth Enzymol 10:41-7. - »Bioblast link«
  5. Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. Respir Physiol 128:277-97. - »Bioblast link«
  6. Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. doi:10.26124/bec:2020-0001.v1. - »Bioblast link«
  7. 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. Biochim Biophys Acta 1365:249-54. - »Bioblast link« - Oxygen kinetics is different in the LEAK state without adenylates (LN) and State 4 (LEAK state with ATP, LN).
  8. Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. Proc Natl Acad Sci U S A 97:11080-5. - »Bioblast link«
  9. König T, Nicholls DG, Garland PB (1969) The inhibition of pyruvate and Ls(+)-isocitrate oxidation by succinate oxidation in rat liver mitochondria. Biochem J 114:589-96. - »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?
  10. 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. Methods Enzymol 542:163-81. - »Bioblast link«
  11. Singh Simon (1997) Fermat's last theorem. Fourth Estate, London 340 pp. - »Bioblast link«
Fig. 2.4.

Notes: Coupling states

» MitoPedia: Respiratory states OXPHOS ROUTINE ET capacity LEAK - ROX
  1. 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.
  2. H+ translocation through pumps is shown by dotted arrows across the mtIM.
Gnaiger 2020 BEC MitoPathways

Chapter 3. Normalization of rate: flow, flux, and flux ratios

References: 3. Normalization

  1. 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. Biochim Biophys Acta 1797:557-65. - »Bioblast link« - Tables 3.1 and 3.2: HEK 293
  2. Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. J Biol Chem 217:383-93. - »Bioblast link«
  3. Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem 217:409-27. - »Bioblast link«
  4. 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. Methods Mol Biol 1782:31-70. - »Bioblast link«
  5. Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. Respir Physiol 128:277-97. - »Bioblast link«
  6. 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. Biochem J 380:919-28. - »Bioblast link« - Tables 3.1 and 3.2: fibrolasts; Figure 3.1.
  7. Hütter E, Unterluggauer H, Garedew A, Jansen-Dürr P, Gnaiger E (2006) High-resolution respirometry - a modern tool in aging research. Exp Gerontol 41:103-9. - »Bioblast link«
  8. 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. Biochim Biophys Acta 1642:115-23. - »Bioblast link« - Tables 3.1 and 3.2: CEM
  9. 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. Cell Biochem Biophys 44:179-86. - »Bioblast link«


Questions.jpg


Click to expand or collaps
Bioblast links: Coupling control - >>>>>>> - Click on [Expand] or [Collapse] - >>>>>>>

Mitochondrial and cellular respiratory rates in coupling-control states

OXPHOS-coupled energy cycles. Source: The Blue Book
» Baseline state
Respiratory rate Definition Icon
OXPHOS capacity P = -Rox P.jpg mt-preparations
ROUTINE respiration R = -Rox R.jpg living cells
ET capacity E = -Rox E.jpg » Level flow
» Noncoupled respiration - Uncoupler
LEAK respiration L = -Rox L.jpg » Static head
» LEAK state with ATP
» LEAK state with oligomycin
» LEAK state without adenylates
Residual oxygen consumption Rox L = -Rox ROX.jpg
  • Chance and Williams nomenclature: respiratory states
» State 1 —» State 2 —» State 3 —» State 4 —» State 5

Flux control ratios related to coupling in mt-preparations and living cells

» Flux control ratio
» Coupling-control ratio
» Coupling-control protocol
FCR Definition Icon
L/P coupling-control ratio L/P L/P coupling-control ratio » Respiratory acceptor control ratio, RCR = P/L
L/R coupling-control ratio L/R L/R coupling-control ratio
L/E coupling-control ratio L/E L/E coupling-control ratio » Uncoupling-control ratio, UCR = E/L
P/E control ratio P/E P/E control ratio
R/E control ratio R/E R/E control ratio
net P/E control ratio (P-L)/E net P/E control ratio
net R/E control ratio (R-L)/E net R/E control ratio

Net, excess, and reserve capacities of respiration

Respiratory net rate Definition Icon
P-L net OXPHOS capacity P-L P-L net OXPHOS  capacity
R-L net ROUTINE capacity R-L R-L net ROUTINE capacity
E-L net ET capacity E-L E-L net ET capacity
E-P excess capacity E-P E-P excess capacity
E-R reserve capacity E-R E-R reserve capacity

Flux control efficiencies related to coupling-control ratios

» Flux control efficiency jZ-Y
» Background state
» Reference state
» Metabolic control variable
Coupling-control efficiency Definition Icon Canonical term
P-L control efficiency jP-L = (P-L)/P = 1-L/P P-L control efficiency P-L OXPHOS-flux control efficiency
R-L control efficiency jR-L = (R-L)/R = 1-L/R R-L control efficiency R-L ROUTINE-flux control efficiency
E-L coupling efficiency jE-L = (E-L)/E = 1-L/E E-L coupling efficiency E-L ET-coupling efficiency » Biochemical coupling efficiency
E-P control efficiency jE-P = (E-P)/E = 1-P/E E-P control efficiency E-P ET-excess flux control efficiency
E-R control efficiency jE-R = (E-R)/E = 1-R/E E-R control efficiency E-R ET-reserve flux control efficiency

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


Figure 4.3.
Gnaiger 2020 BEC MitoPathways

Chapter 4. NADH-linked pathways through Complex I: respiratory pathway control with pruvate, glutamate, malate

References: 4. N-pathways

  1. Brandt U (2006) Energy converting NADH:quinone oxidoreductase (Complex I). Annu Rev Biochem 75:69-92.
  2. Brewer GJ, Jones TT, Wallimann T, Schlattner U (2004) Higher respiratory rates and improved creatine stimulation in brain mitochondria isolated with antioxidants. Mitochondrion 4:49-57. - »Bioblast link«
  3. Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem 217:409-27. - »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.
  4. Digerness SB, Reddy WJ (1976) The malate-aspartate shuttle in heart mitochondria. J Mol Cell Cardiol. 8:779-85.
  5. 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.
  6. Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41:1837–45. - »Bioblast link«
  7. Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. Proc Natl Acad Sci U S A 97:11080-5. - »Bioblast link« - Equilibrium ratio of malate to fumarate is 4.1.
  8. Hildyard JCW, Halestrap AP (2003) Identification of the mitochondrial pyruvate carrier in Saccharomyces cerevidiae. Biochem J 374:607-11.
  9. 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 %.
  10. 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. In What is Controlling Life? (Gnaiger E, Gellerich FN, Wyss M, eds) Modern Trends in BioThermoKinetics 3, Innsbruck Univ Press:226-31. - »Bioblast link« - Glutamate derived from hydrolyzation of glutamine is a very important aerobic substrate in cultured cells.
  11. Lemasters JJ (1984) The ATP-to-oxygen stoichiometries of oxidative phosphorylation by rat liver mitochondria. J Biol Chem 259:13123-30. - »Bioblast link« - Malonate added to inhibit the succinate-fumarate reaction exerts only a minor effect on liver mitochondrial respiration.
  12. 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.
  13. Messer JI, Jackman MR, Willis WT (2004) Pyruvate and citric acid cycle carbon requirements in isolated skeletal muscle mitochondria. Am J Physiol Cell Physiol 286:C565-72. - »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.
  14. Nicholls DG, Ferguson SJ (2002) Bioenergetics 3, Academic Press, London:287 pp. - »Bioblast link« - Carriers.
  15. Ouhabi R, Boue-Grabot M, Mazat J-P (1994) ATP synthesis in permeabilized cells: Assessment of the ATP/O ratios in situ. In What is Controlling Life? (Gnaiger E, Gellerich FN, Wyss M, eds) Modern Trends in BioThermoKinetics 3, Innsbruck Univ Press:141-4. - »Bioblast link« - In fibroblasts, GMP supports a higher respiratory flux than PMP.
  16. O’Donnell JM, Kudej RK, LaNoue KF, Vatner SF, Lewandowski ED (2004) Limited transfer of cytosolic NADH into mitochondria at high cardiac workload. Am J Physiol Heart Circ Physiol 286:H2237-42.
  17. 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. Mitochondrion 4:377-85. - »Bioblast link« - OXPHOS with glutamate alone is 50 % to 85 % of respiration with glutamate&malate. Accumulation of fumarate inhibits succinate dehydrogenase and glutamate dehydrogenase (Caughey et al 1957; Dervartanian, Veeger 1964). - OXPHOS with glutamate&malate is identical or 10 % higher than with pyruvate&malate.
  18. Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. Mol Cell Biochem 208:37-44. - »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.
  19. Schöpf B, Weissensteiner H, Schäfer G, Fazzini F, Charoentong P, Naschberger A, Rupp B, Fendt L, Bukur V, Giese I, Sorn P, Sant’Anna-Silva AC, Iglesias-Gonzalez J, Sahin U, Kronenberg F, Gnaiger E, Klocker H (2020) OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation. Nat Commun 11:1487. - »Bioblast link«
  20. Swenson Erik R (2018) Does aerobic respiration produce carbon dioxide or hydrogen ion and bicarbonate? Anesthesiology 128:873–9. - »Bioblast link«
  21. Thomas et al (2004) - OXPHOS in human skeletal muscle for PMP is 25 % higher than for GMP.
  22. Winkler-Stuck K, Kirches E, Mawrin C, Dietzmann K, Lins H, Wallesch CW, Kunz WS, Wiedemann FR (2005) Re-evaluation of the dysfunction of mitochondrial respiratory chain in skeletal muscle of patients with Parkinson's disease. J Neural Transm 112:499-518. - »Bioblast link« - OXPHOS in human skeletal muscle for PMP is 16% higher than for GMP.
  23. MitoPedia
» Malic enzyme
N-junction

Notes: N-pathways

  1. N-pathway control state
  2. 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.
  3. 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.
  4. 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.
  5. 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.


Fig. 5.1.
Gnaiger 2020 BEC MitoPathways

Chapter 5. S-pathway through Complex II, F-pathway through electron-transferring flavoprotein, Gp-pathway through glycerophosphate dehydrogenase

References: 5. S-, F-, Gp-pathways

  1. Capel F, Rimbert V, Lioger D, Diot A, Rousset P, Patureau Mirand P, Boirie Y, Morio B, Mosoni L (2005) Due to reverse electron transfer, mitochondrial H2O2 release increases with age in human vastus lateralis muscle although oxidative capacity is preserved. Mech Ageing Develop 126:505-11. - With succinate alone OXPHOS is 30-40% lower than with succinate+rotenone in human skeletal muscle mitochondria.
  2. Cecchini G (2003) Function and structure of Complex II of the respiratory chain. Annu Rev Biochem 72:77-109.
  3. Ernster L, Nordenbrand K (1967) Skeletal muscle mitochondria. In: Estabrook RW, Pullman ME (eds) Meth Enzymol:86-94. – With succinate alone OXPHOS is 30-40% lower than with succinate+rotenone in rat skeletal muscle mitochondria.
  4. Jackman MR, Willis WT (1996) Characteristics of mitochondria isolated from type I and type IIb skeletal muscle. Am J Physiol Cell Physiol 270:C673-8. - Glycerophosphate oxidation is 10-fold higher in rabbit gracilis mitochondria compared to soleus.
  5. Lehninger AL (1970) Biochemistry. The molecular basis of cell structure and function Worth:833 pp. - Oxaloacetate is a more potent competitive inhibitor of succinate dehydrogenase than malonate even at small concentration (p 352).
  6. Muller FL, Liu Y, Abdul-Ghani MA, Lustgarten MS, Bhattacharya A, Jang YC, Van Remmen H (2008) High rates of superoxide production in skeletal-muscle mitochondria respiring on both Complex I- and Complex II-linked substrates. Biochem J 409:491–9. - »Bioblast link« - Addition of malate inhibits superoxide production with succinate, probably due to the oxaloacetate inhibition of CII.
  7. Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. Mol Cell Biochem 208:37-44. - »Bioblast link« – Glycerophosphate oxidation is relatively slow.
  8. Rauchova H, Drahota Z, Rauch P, Fato R, Lenaz G (2003) Coenzyme Q releases the inhibitory effect of free fatty acids on mitochondrial glycerophosphate dehydrogenase. Acta Biochim Polonica 50:405-13. - Glycerophosphate is an important substrate for respiration in brown adipose tissue mitochondria.
  9. Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z (2005) Crystal structure of mitochondrial respiratory membrane protein Complex II. Cell 121:1043–57.
  10. MitoPedia
» Complex II-linked substrate state •• Complex II
» Glycerophosphate dehydrogenase complex •• Electron-transferring flavoprotein complex
Succinate

Notes: S-, F-, Gp-pathways

  1. Succinate pathway
  2. 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.
Gnaiger 2020 BEC MitoPathways
Fig. 5.4.

Chapter 6. NS-pathway through Complexes CI & CII: convergent electron transfer at the Q-junction and additive effect of substrate combinations

References: 6. Q-junction

  1. Aragonés J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, Dirkx R, Zacchigna S, Lemieux H, Jeoung NH, Lambrechts D, Bishop T, Lafuste P, Diez-Juan A, K Harten S, Van Noten P, De Bock K, Willam C, Tjwa M, Grosfeld A, Navet R, Moons L, Vandendriessche T, Deroose C, Wijeyekoon B, Nuyts J, Jordan B, Silasi-Mansat R, Lupu F, Dewerchin M, Pugh C, Salmon P, Mortelmans L, Gallez B, Gorus F, Buyse J, Sluse F, Harris RA, Gnaiger E, Hespel P, Van Hecke P, Schuit F, Van Veldhoven P, Ratcliffe P, Baes M, Maxwell P, Carmeliet P (2008) Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 40:170-80. - »Bioblast link« - OXPHOS analysis for phenotyping.
  2. Bianchi C, Genova ML, Parenti Castelli G, Lenaz G (2004) The mitochondrial respiratory chain is partially organized in a supercomplex assembly: kinetic evidence using flux control analysis. J Biol Chem 279:36562-9. - »Bioblast link«
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  57. MitoPedia
NS-pathway control state

Notes: Q-junction

  1. NS-pathway control state
  2. 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).


Gnaiger 2020 BEC MitoPathways

Chapter 7. Additivity of convergent electron transfer

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Gnaiger 2020 BEC MitoPathways
Vector flux and velocity

Chapter 8. Protonmotive pressure and respiratory control

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Gnaiger 2020 BEC MitoPathways

A. Conversions of metabolic fluxes

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Gnaiger 2020 BEC MitoPathways

B: SUIT

B1. Substrates, uncouplers and inhibitors

» MitoPedia: Substrates and metabolites
» MitoPedia: Uncouplers
» MitoPedia: Inhibitors
Gnaiger 2020 BEC MitoPathways

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
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 Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1.


Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. doi:10.26124/bec:2020-0001.v1.
  • Komlodi et al (2021) Simultaneous measurement of respiration and redox state of the Coenzyme Q pool in mitochondrial preparations. MitoFit Preprints 2021.2. doi:10.26124/mitofit:2021-0002
  • Cardoso et al (2021) Magnesium Green for fluorometric measurement of ATP production does not interfere with mitochondrial respiration. MitoFit Preprints 2021. doi:10.26124/mitofit:2021-0001
  • Huete-Ortega et al (2021) Substrate-uncoupler-inhibitor-titration protocols for dark respiration in Chlamydomonas reinhardtii. MitoFit Preprints 2021 (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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