Regulation of Mitochondrial Respiration in Liver

  • Arthur J. Verhoeven
  • Carlo W. T. van Roermund
  • Peter J. A. M. Plomp
  • Ronald J. A. Wanders
  • Albert K. Groen
  • Joseph M. Tager
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 194)


In studies on the control of mitochondrial respiration carried out in the past 10 years, particular attention has been focussed on cytochrome c oxidase and the adenine nucleotide translocator as rate-controlling steps. On the basis of the observation that the first two phosphorylation sites of the respiratory chain are in near equilibrium with the extramitochondrial phosphate potential, Wilson and coworkers1–5 have concluded that regulation of respiration occurs at the cytochrome c oxidase step, the effective rate of this reaction being dependent on the extramitochondrial phosphate potential. According to this model, the adenine nucleotide translocator does not exert significant control on respiration. In contrast, Davis and coworkers6–8, Kunz and coworkers9–11, Lemasters and Sowers12, and our own group13, 14 have concluded that the adenine nucleotide trans-locator is a rate-controlling step for mitochondrial oxidative phosphorylation. The uncertainty about the precise role of the adenine nucleotide translocator and of the cytochrome c oxidase step in controlling respiration is due to the difficulty of quantifying the contribution of various steps to control of a metabolic pathway such as mitochondrial oxidative phosphorylation. Kacser and Burns15–17 and Heinrich and Rapoport18–20 have developed a theoretical framework for quantifying the amount of control that a particular step in a metabolic pathway exerts on flux through that pathway.


Thyroid Hormone Oxygen Uptake Mitochondrial Respiration Liver Mitochondrion Adenine Nucleotide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. Erecinscka, R.L. Veech and D.F. Wilson, Thermodynamic relationships between the oxidation-reduction reactions and the ATP synthesis in suspensions of isolated pigeon heart mitochondria, Arch. Biochem. Biophys. 160: 412–421 (1974).CrossRefGoogle Scholar
  2. 2.
    D.F. Wilson, M. Stubbs, N. Oshino and M. Erecifiska, Thermodynamic relationships between the mitochondrial oxidation-reduction reactions and cellular ATP levels in ascites tumor cells and perfused rat liver, Biochemistry 13: 5305–5311 (1974).PubMedCrossRefGoogle Scholar
  3. 3.
    D.F. Wilson, M. Stubbs, R.L. Veech, M. Erecifiska and H.A. Krebs, Equilibrium relations between the oxidation-reduction reactions and the adenosine triphosphate synthesis in suspensions of isolated liver cells, Biochem. J. 140: 57–64 (1974).PubMedGoogle Scholar
  4. 4.
    N.G. Forman and D.F. Wilson, Energetics and stoichiometry of oxidative phosphorylation from NADH to cytochrome c in isolated rat liver mitochondria, J. Biol. Chem. 257: 12908–12915 (1982).PubMedGoogle Scholar
  5. 5.
    N.G. Forman and D.F. Wilson, Dependence of mitochondrial oxidative phosphorylation on activity of the adenine nucleotide translocase, J. Biol. Chem. 258: 8649–8655 (1983)PubMedGoogle Scholar
  6. 6.
    E.J. Davis, L. Lumeng and D. Bottoms, On the relationships between the stoichiometry of oxidative phosphorylation and the phosphorylation potential of rat liver mitochondria as functions of respiratory state, FEBS Lett. 39: 9–12 (1974).PubMedCrossRefGoogle Scholar
  7. 7.
    E.J. Davis and L. Lumeng, Relationships between the phosphorylation potentials generated by liver mitochondria and respiratory state under conditions of adenosine diphosphate control, J. Biol. Chem. 250: 2275–2282 (1975).Google Scholar
  8. 8.
    E.J. Davis and W.I.A. Davis-van Thienen, Control of mitochondrial metabolism by the ATP/ADP ratio, Biochem. Biophys. Res. Commun. 83: 1260–1266 (1978).CrossRefGoogle Scholar
  9. 9.
    U. Küster, R. Bohnensack and W. Kunz, Control of oxidative phosphorylation by the extramitochondrial ATP/ADP ratio, Biochim. Biophys. Acta 440: 391–402 (1976).CrossRefGoogle Scholar
  10. 10.
    G. Letko, U. Küster, J. Duszynski and W. Kunz, Investigation of the dependence of the intramitochondrial [ATP]/[ADP] ratio on the respiration rate, Biochim. Biophys. Acta 593: 196–203 (1980).PubMedCrossRefGoogle Scholar
  11. 11.
    W. Kunz, R. Bohnensack, G. Böhme, U. Küster, G. Letko and P. Schönfeld, Relations between extramitochondrial and intramitochondrial adenine nucleotide systems, Arch. Biochem. Biophys. 209: 219–229 (1981).PubMedCrossRefGoogle Scholar
  12. 12.
    J.J. Lemasters and A.E. Sowers, Phosphate dependence and atractyloside inhibition of mitochondrial oxidative phosphorylation. The ADP-ATP carrier is rate-limiting. J. Biol. Chem. 254: 1248–1251 (1979).PubMedGoogle Scholar
  13. 13.
    T.P.M. Akerboom, H. Bookelman and J.M. Tager, Control of ATP transport across the mitochondrial membrane in isolated rat-liver cells, FEBS Lett. 74: 50–54 (1977).PubMedCrossRefGoogle Scholar
  14. 14.
    R. van der Meer, T.P.M. Akerboom, A.K. Groen and J.M. Tager, Relationship between oxygen uptake of perifused rat-liver cells and the cytosolic phosphorylation state calculated from indicator metabolites and a redetermined equilibrium constant, Eur. J. Biochem. 84: 421–428 (1978).PubMedCrossRefGoogle Scholar
  15. 15.
    H. Kacser and J.A. Burns, The control of flux, in: “Rate Control of Biological Processes”, D.D. Davies, ed., pp. 65–104, Cambridge University Press, London (1973).Google Scholar
  16. 16.
    H. Kacser and J.A. Burns, Molecular democracy: who shares the controls?,Biochem. Soc. Trans. 7: 1149–1161 (1979).PubMedGoogle Scholar
  17. 17.
    H. Kacser and J.A. Burns, The molecular basis of dominance, Genetics 97: 639–666 (1981).PubMedGoogle Scholar
  18. 18.
    R. Heinrich and T.A. Rapoport, A linear steady-state treatment of enzymatic chains. General properties, control and effector strength, Eur. J. Biochem. 42: 89–95 (1974).PubMedCrossRefGoogle Scholar
  19. 19.
    R. Heinrich and T.A. Rapoport, A linear steady-state treatment of enzymatic chains. Critique of the crossover theorem and a general procedure to identify interactions with an effector, Eur. J. Biochem. 42: 97–105 (1974).PubMedCrossRefGoogle Scholar
  20. 20.
    R. Heinrich and T.A. Rapoport, Mathematical analysis of multi-enzyme systems. II. Steady state and transient control, Biosystems 7: 130–136 (1975).PubMedCrossRefGoogle Scholar
  21. 21.
    H.V. Westerhoff, A.K. Groen, R.J.A. Wanders and J.M. Tager, Modern theories of metabolic control and their applications, Bioscience Rep. (1984) in press.Google Scholar
  22. 22.
    A.K. Groen, R.J.A. Wanders, H.V. Westerhoff, R. van der Meer and J.M. Tager, Quantification of the contribution of various steps to the control of mitochondrial respiration, J. Biol. Chem. 257: 2754–2757 (1982).PubMedGoogle Scholar
  23. 23.
    J. Duszynski, A.K. Groen, R.J.A. Wanders, R.C. Vervoorn and J.M. Tager, Quantification of the role of the adenine nucleotide translocator in the control of mitochondrial respiration in isolated rat-liver cells, FEBS Lett. 146: 262–266 (1982).PubMedCrossRefGoogle Scholar
  24. 24.
    R.K. Yamazaki, Glucagon stimulation of mitochondrial respiration, J. Biol. Chem. 250: 7924–7930 (1975).PubMedGoogle Scholar
  25. 25.
    M.A. Titheradge and R.C. Haynes, The hormonal stimulation of ureogenesis in isolated hepatocytes through increases in mitochondrial ATP production, Arch. Biochem. Biophys. 201: 44–55 (1980).PubMedCrossRefGoogle Scholar
  26. 26.
    M.A. Titheradge and H.G. Coore, Hormonal regulation of liver mitochondrial pyruvate carrier in relation to gluconeogenesis and lipogenesis, FEBS Lett. 71: 73–78 (1976).CrossRefGoogle Scholar
  27. 27.
    E.H. Allan, A.B. Chisholm and M.A. Titheradge, The stimulation of hepatic oxidative phosphorylation following dexamethasone treatment of rats, Biochim. Biophys. Acta 725: 71–76 (1983).PubMedCrossRefGoogle Scholar
  28. 28.
    V.T. Maddaiah, S. Clejan, A.G. Palekar and P.J. Collipp, Hormones and liver mitochondria: effects of growth hormone and thyroxine on respiration, fluorescence of 1-anilino-8-naphthalene sulfonate and enzyme activities of complex I and II of submitochondrial particles, Arch. Biochem. Biophys. 210: 666–677 (1981).PubMedCrossRefGoogle Scholar
  29. 29.
    E.A. Siess and O.H. Wieland, Glucagon-induced stimulation of 2-oxoglutarate metabolism in mitochondria from rat liver, FEBS Lett. 93: 301–306 (1978).PubMedCrossRefGoogle Scholar
  30. 30.
    E.A. Siess and O.H. Wieland, Isolated hepatocytes as a model for the study of stable glucagon effects on mitochondrial respiratory functions, FEBS Lett. 101: 277–281 (1979).PubMedCrossRefGoogle Scholar
  31. 31.
    M.A. Titheradge and R.C. Haynes, Glucagon treatment stimulates the oxidation of durohydroquinone by rat liver mitochondria, FEBS Lett. 106: 330–334 (1979).PubMedCrossRefGoogle Scholar
  32. 32.
    B.M. Babior, S. Creagan, S.H. Ingbar and R.S. Kipnes, Stimulation of mitochondrial adenosine diphosphate uptake by thyroid hormones, Proc. Nat. Acad. Sci. USA 70: 98–102 (1973).PubMedCrossRefGoogle Scholar
  33. 33.
    J. BryZa, E.J. Harris and J.A. Plumb, The stimulatory effect of glucagon and dibutyryl cyclic AMP on ureogenesis and gluconeogenesis in relation to the mitochondrial ATP content, FEBS Lett. 80: 443–448 (1980).Google Scholar
  34. 34.
    A.P. Halestrap, The nature of the stimulation of the respiratory chain of rat liver mitochondria by glucagon pretreatment of animals, Biochem. J. 204: 37–47 (1982).PubMedGoogle Scholar
  35. 35.
    J.A. Berden and E.C. Slater, The allosteric binding of antimycin to cytochrome b in the mitochondrial membrane, Biochim. Biophys. Acta 256: 199–215 (1972).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Arthur J. Verhoeven
    • 1
  • Carlo W. T. van Roermund
    • 1
  • Peter J. A. M. Plomp
    • 1
  • Ronald J. A. Wanders
    • 1
  • Albert K. Groen
    • 1
  • Joseph M. Tager
    • 1
  1. 1.Laboratory of Biochemistry, B.C.P. Jansen InstituteUniversity of AmsterdamAmsterdamThe Netherlands

Personalised recommendations