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. 2000 Dec;79(6):2785–2800. doi: 10.1016/S0006-3495(00)76518-0

Metabolically derived potential on the outer membrane of mitochondria: a computational model.

S V Lemeshko 1, V V Lemeshko 1
PMCID: PMC1301160  PMID: 11106589

Abstract

The outer mitochondrial membrane (OMM) is permeable to various small substances because of the presence of a voltage-dependent anion channel (VDAC). The voltage dependence of VDAC's permeability is puzzling, because the existence of membrane potential on the OMM has never been shown. We propose that steady-state metabolically derived potential (MDP) may be generated on the OMM as the result of the difference in its permeability restriction for various charged metabolites. To demonstrate the possibility of MDP generation, two models were considered: a liposomal model and a simplified cell model with a creatine kinase energy channeling system. Quantitative computational analysis of the simplified cell model shows that a MDP of up to -5 mV, in addition to the Donnan potential, may be generated at high workloads, even if the OMM is highly permeable to small inorganic ions, including potassium. Calculations show that MDP and DeltapH, generated on the OMM, depend on the cytoplasmic pH and energy demand rate. Computational modeling suggests that MDP may be important for cell energy metabolism regulation in multiple ways, including VDAC's permeability modulation and the effect of electrodynamic compartmentation. The osmotic pressure difference between the mitochondrial intermembrane space and the cytoplasm, as related to the electrodynamic compartmentation effects, might explain the morphological changes in mitochondria under intense workloads.

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Selected References

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  1. Aliev M. K., Saks V. A. Mathematical modeling of intracellular transport processes and the creatine kinase systems: a probability approach. Mol Cell Biochem. 1994 Apr-May;133-134:333–346. [PubMed] [Google Scholar]
  2. Benz R., Kottke M., Brdiczka D. The cationically selective state of the mitochondrial outer membrane pore: a study with intact mitochondria and reconstituted mitochondrial porin. Biochim Biophys Acta. 1990 Mar;1022(3):311–318. doi: 10.1016/0005-2736(90)90279-w. [DOI] [PubMed] [Google Scholar]
  3. Brdiczka D., Wallimann T. The importance of the outer mitochondrial compartment in regulation of energy metabolism. Mol Cell Biochem. 1994 Apr-May;133-134:69–83. doi: 10.1007/BF01267948. [DOI] [PubMed] [Google Scholar]
  4. Báthori G., Szabó I., Schmehl I., Tombola F., Messina A., De Pinto V., Zoratti M. Novel aspects of the electrophysiology of mitochondrial porin. Biochem Biophys Res Commun. 1998 Feb 4;243(1):258–263. doi: 10.1006/bbrc.1997.7926. [DOI] [PubMed] [Google Scholar]
  5. Colombini M. A candidate for the permeability pathway of the outer mitochondrial membrane. Nature. 1979 Jun 14;279(5714):643–645. doi: 10.1038/279643a0. [DOI] [PubMed] [Google Scholar]
  6. Colombini M., Blachly-Dyson E., Forte M. VDAC, a channel in the outer mitochondrial membrane. Ion Channels. 1996;4:169–202. doi: 10.1007/978-1-4899-1775-1_5. [DOI] [PubMed] [Google Scholar]
  7. Colombini M., Yeung C. L., Tung J., König T. The mitochondrial outer membrane channel, VDAC, is regulated by a synthetic polyanion. Biochim Biophys Acta. 1987 Dec 11;905(2):279–286. doi: 10.1016/0005-2736(87)90456-1. [DOI] [PubMed] [Google Scholar]
  8. Crompton M., Costi A., Hayat L. Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria. Biochem J. 1987 Aug 1;245(3):915–918. doi: 10.1042/bj2450915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hansford R. G. Physiological role of mitochondrial Ca2+ transport. J Bioenerg Biomembr. 1994 Oct;26(5):495–508. doi: 10.1007/BF00762734. [DOI] [PubMed] [Google Scholar]
  10. Hodge T., Colombini M. Regulation of metabolite flux through voltage-gating of VDAC channels. J Membr Biol. 1997 Jun 1;157(3):271–279. doi: 10.1007/s002329900235. [DOI] [PubMed] [Google Scholar]
  11. Holden M. J., Colombini M. The outer mitochondrial membrane channel, VDAC, is modulated by a protein localized in the intermembrane space. Biochim Biophys Acta. 1993 Oct 4;1144(3):396–402. doi: 10.1016/0005-2728(93)90126-z. [DOI] [PubMed] [Google Scholar]
  12. Landolfi B., Curci S., Debellis L., Pozzan T., Hofer A. M. Ca2+ homeostasis in the agonist-sensitive internal store: functional interactions between mitochondria and the ER measured In situ in intact cells. J Cell Biol. 1998 Sep 7;142(5):1235–1243. doi: 10.1083/jcb.142.5.1235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lee A. C., Xu X., Colombini M. The role of pyridine dinucleotides in regulating the permeability of the mitochondrial outer membrane. J Biol Chem. 1996 Oct 25;271(43):26724–26731. doi: 10.1074/jbc.271.43.26724. [DOI] [PubMed] [Google Scholar]
  14. Lemeshko V. V., Shekh V. E. Hypotonic fragility of outer membrane and activation of external pathway of NADH oxidation in rat liver mitochondria are increased with age. Mech Ageing Dev. 1993 May;68(1-3):221–233. doi: 10.1016/0047-6374(93)90153-i. [DOI] [PubMed] [Google Scholar]
  15. Lemeshko V. V. Zavisimost' strukturnoi labil'nosti naryzhnoi membrany mitokhondrii pecheni ot vozrasta i pola krys. Biofizika. 1982 Sep-Oct;27(5):837–840. [PubMed] [Google Scholar]
  16. Lindén M., Andersson G., Gellerfors P., Nelson B. D. Subcellular distribution of rat liver porin. Biochim Biophys Acta. 1984 Feb 29;770(1):93–96. doi: 10.1016/0005-2736(84)90077-4. [DOI] [PubMed] [Google Scholar]
  17. Lipskaya TYu, Geiger P. J., Bessman S. P. Compartmentation and metabolic parameters of mitochondrial hexokinase and creatine kinase depend on the rate of oxidative phosphorylation. Biochem Mol Med. 1995 Aug;55(2):81–89. doi: 10.1006/bmme.1995.1037. [DOI] [PubMed] [Google Scholar]
  18. Liu M. Y., Colombini M. A soluble mitochondrial protein increases the voltage dependence of the mitochondrial channel, VDAC. J Bioenerg Biomembr. 1992 Feb;24(1):41–46. doi: 10.1007/BF00769529. [DOI] [PubMed] [Google Scholar]
  19. Liu M. Y., Colombini M. Regulation of mitochondrial respiration by controlling the permeability of the outer membrane through the mitochondrial channel, VDAC. Biochim Biophys Acta. 1992 Jan 16;1098(2):255–260. doi: 10.1016/s0005-2728(05)80344-5. [DOI] [PubMed] [Google Scholar]
  20. Liu M. Y., Colombini M. Voltage gating of the mitochondrial outer membrane channel VDAC is regulated by a very conserved protein. Am J Physiol. 1991 Feb;260(2 Pt 1):C371–C374. doi: 10.1152/ajpcell.1991.260.2.C371. [DOI] [PubMed] [Google Scholar]
  21. Lomax R. B., Robertson W. R. Mitochondrial alpha-glycerol phosphate dehydrogenase activity in IIA fibres of the rat lateral gastrocnemius muscle; the effect of Ca2+ and ATP. Histochem J. 1990 Feb;22(2):119–124. doi: 10.1007/BF01885791. [DOI] [PubMed] [Google Scholar]
  22. Mangan P. S., Colombini M. Ultrasteep voltage dependence in a membrane channel. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4896–4900. doi: 10.1073/pnas.84.14.4896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mannella C. A., Forte M., Colombini M. Toward the molecular structure of the mitochondrial channel, VDAC. J Bioenerg Biomembr. 1992 Feb;24(1):7–19. doi: 10.1007/BF00769525. [DOI] [PubMed] [Google Scholar]
  24. Mannella C. A. Structure of the outer mitochondrial membrane: ordered arrays of porelike subunits in outer-membrane fractions from Neurospora crassa mitochondria. J Cell Biol. 1982 Sep;94(3):680–687. doi: 10.1083/jcb.94.3.680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McCormack J. G. Evidence that adrenaline activates key oxidative enzymes in rat liver by increasing intramitochondrial [Ca2+]. FEBS Lett. 1985 Jan 28;180(2):259–264. doi: 10.1016/0014-5793(85)81082-6. [DOI] [PubMed] [Google Scholar]
  26. O'Gorman E., Beutner G., Wallimann T., Brdiczka D. Differential effects of creatine depletion on the regulation of enzyme activities and on creatine-stimulated mitochondrial respiration in skeletal muscle, heart, and brain. Biochim Biophys Acta. 1996 Sep 12;1276(2):161–170. doi: 10.1016/0005-2728(96)00074-6. [DOI] [PubMed] [Google Scholar]
  27. Rostovtseva T. K., Bezrukov S. M. ATP transport through a single mitochondrial channel, VDAC, studied by current fluctuation analysis. Biophys J. 1998 May;74(5):2365–2373. doi: 10.1016/S0006-3495(98)77945-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rostovtseva T., Colombini M. VDAC channels mediate and gate the flow of ATP: implications for the regulation of mitochondrial function. Biophys J. 1997 May;72(5):1954–1962. doi: 10.1016/S0006-3495(97)78841-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Saks V. A., Aliev M. K. Is there the creatine kinase equilibrium in working heart cells? Biochem Biophys Res Commun. 1996 Oct 14;227(2):360–367. doi: 10.1006/bbrc.1996.1513. [DOI] [PubMed] [Google Scholar]
  30. Saks V. A., Khuchua Z. A., Vasilyeva E. V., Belikova OYu, Kuznetsov A. V. Metabolic compartmentation and substrate channelling in muscle cells. Role of coupled creatine kinases in in vivo regulation of cellular respiration--a synthesis. Mol Cell Biochem. 1994 Apr-May;133-134:155–192. doi: 10.1007/BF01267954. [DOI] [PubMed] [Google Scholar]
  31. Saks V. A., Kuznetsov A. V., Khuchua Z. A., Vasilyeva E. V., Belikova J. O., Kesvatera T., Tiivel T. Control of cellular respiration in vivo by mitochondrial outer membrane and by creatine kinase. A new speculative hypothesis: possible involvement of mitochondrial-cytoskeleton interactions. J Mol Cell Cardiol. 1995 Jan;27(1):625–645. doi: 10.1016/s0022-2828(08)80056-9. [DOI] [PubMed] [Google Scholar]
  32. Saks V. A., Kuznetsov A. V., Kupriyanov V. V., Miceli M. V., Jacobus W. E. Creatine kinase of rat heart mitochondria. The demonstration of functional coupling to oxidative phosphorylation in an inner membrane-matrix preparation. J Biol Chem. 1985 Jun 25;260(12):7757–7764. [PubMed] [Google Scholar]
  33. Saks V. A., Vasil'eva E., Belikova YuO, Kuznetsov A. V., Lyapina S., Petrova L., Perov N. A. Retarded diffusion of ADP in cardiomyocytes: possible role of mitochondrial outer membrane and creatine kinase in cellular regulation of oxidative phosphorylation. Biochim Biophys Acta. 1993 Sep 13;1144(2):134–148. doi: 10.1016/0005-2728(93)90166-d. [DOI] [PubMed] [Google Scholar]
  34. Schein S. J., Colombini M., Finkelstein A. Reconstitution in planar lipid bilayers of a voltage-dependent anion-selective channel obtained from paramecium mitochondria. J Membr Biol. 1976 Dec 28;30(2):99–120. doi: 10.1007/BF01869662. [DOI] [PubMed] [Google Scholar]
  35. Smith H. E., Page E. Morphometry of rat heart mitochondrial subcompartments and membranes: application to myocardial cell atrophy after hypophysectomy. J Ultrastruct Res. 1976 Apr;55(1):31–41. doi: 10.1016/s0022-5320(76)80079-2. [DOI] [PubMed] [Google Scholar]
  36. Sorgato M. C., Moran O. Channels in mitochondrial membranes: knowns, unknowns, and prospects for the future. Crit Rev Biochem Mol Biol. 1993;28(2):127–171. doi: 10.3109/10409239309086793. [DOI] [PubMed] [Google Scholar]
  37. Tian R., Ingwall J. S. Energetic basis for reduced contractile reserve in isolated rat hearts. Am J Physiol. 1996 Apr;270(4 Pt 2):H1207–H1216. doi: 10.1152/ajpheart.1996.270.4.H1207. [DOI] [PubMed] [Google Scholar]
  38. Wallimann T., Wyss M., Brdiczka D., Nicolay K., Eppenberger H. M. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis. Biochem J. 1992 Jan 1;281(Pt 1):21–40. doi: 10.1042/bj2810021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Zimmerberg J., Parsegian V. A. Polymer inaccessible volume changes during opening and closing of a voltage-dependent ionic channel. Nature. 1986 Sep 4;323(6083):36–39. doi: 10.1038/323036a0. [DOI] [PubMed] [Google Scholar]
  40. Zizi M., Byrd C., Boxus R., Colombini M. The voltage-gating process of the voltage-dependent anion channel is sensitive to ion flow. Biophys J. 1998 Aug;75(2):704–713. doi: 10.1016/S0006-3495(98)77560-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zizi M., Thomas L., Blachly-Dyson E., Forte M., Colombini M. Oriented channel insertion reveals the motion of a transmembrane beta strand during voltage gating of VDAC. J Membr Biol. 1995 Mar;144(2):121–129. doi: 10.1007/BF00232798. [DOI] [PubMed] [Google Scholar]

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