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. 2002 Feb;82(2):684–692. doi: 10.1016/S0006-3495(02)75431-3

Model of the outer membrane potential generation by the inner membrane of mitochondria.

Victor V Lemeshko 1
PMCID: PMC1301878  PMID: 11806911

Abstract

Voltage-dependent anion channels in the outer mitochondrial membrane are strongly regulated by electrical potential. In this work, one of the possible mechanisms of the outer membrane potential generation is proposed. We suggest that the inner membrane potential may be divided on two resistances in series, the resistance of the contact sites between the inner and outer membranes and the resistance of the voltage-dependent anion channels localized beyond the contacts in the outer membrane. The main principle of the proposed mechanism is illustrated by simplified electric and kinetic models. Computational behavior of the kinetic model shows a restriction of the steady-state metabolite flux through the mitochondrial membranes at relatively high concentration of the external ADP. The flux restriction was caused by a decrease of the voltage across the contact sites and by an increase in the outer membrane potential (up to +60 mV) leading to the closure of the voltage-dependent anion channels localized beyond the contact sites. This mechanism suggests that the outer membrane potential may arrest ATP release through the outer membrane beyond the contact sites, thus tightly coordinating mitochondrial metabolism and aerobic glycolysis in tumor and normal proliferating cells.

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Selected References

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  1. Benz R., Brdiczka D. The cation-selective substate of the mitochondrial outer membrane pore: single-channel conductance and influence on intermembrane and peripheral kinases. J Bioenerg Biomembr. 1992 Feb;24(1):33–39. doi: 10.1007/BF00769528. [DOI] [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. Benz R. Porin from bacterial and mitochondrial outer membranes. CRC Crit Rev Biochem. 1985;19(2):145–190. doi: 10.3109/10409238509082542. [DOI] [PubMed] [Google Scholar]
  4. Benz R., Wojtczak L., Bosch W., Brdiczka D. Inhibition of adenine nucleotide transport through the mitochondrial porin by a synthetic polyanion. FEBS Lett. 1988 Apr 11;231(1):75–80. doi: 10.1016/0014-5793(88)80706-3. [DOI] [PubMed] [Google Scholar]
  5. Beutner G., Rück A., Riede B., Brdiczka D. Complexes between hexokinase, mitochondrial porin and adenylate translocator in brain: regulation of hexokinase, oxidative phosphorylation and permeability transition pore. Biochem Soc Trans. 1997 Feb;25(1):151–157. doi: 10.1042/bst0250151. [DOI] [PubMed] [Google Scholar]
  6. Brdiczka D., Beutner G., Rück A., Dolder M., Wallimann T. The molecular structure of mitochondrial contact sites. Their role in regulation of energy metabolism and permeability transition. Biofactors. 1998;8(3-4):235–242. doi: 10.1002/biof.5520080311. [DOI] [PubMed] [Google Scholar]
  7. Brdiczka D. Contact sites between mitochondrial envelope membranes. Structure and function in energy- and protein-transfer. Biochim Biophys Acta. 1991 Nov 13;1071(3):291–312. doi: 10.1016/0304-4157(91)90018-r. [DOI] [PubMed] [Google Scholar]
  8. Brdiczka D. Interaction of mitochondrial porin with cytosolic proteins. Experientia. 1990 Feb 15;46(2):161–167. doi: 10.1007/BF02027312. [DOI] [PubMed] [Google Scholar]
  9. Brustovetsky N., Becker A., Klingenberg M., Bamberg E. Electrical currents associated with nucleotide transport by the reconstituted mitochondrial ADP/ATP carrier. Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):664–668. doi: 10.1073/pnas.93.2.664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Colombini M. Voltage gating in the mitochondrial channel, VDAC. J Membr Biol. 1989 Oct;111(2):103–111. doi: 10.1007/BF01871775. [DOI] [PubMed] [Google Scholar]
  12. Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999 Jul 15;341(Pt 2):233–249. [PMC free article] [PubMed] [Google Scholar]
  13. Denis-Pouxviel C., Riesinger I., Bühler C., Brdiczka D., Murat J. C. Regulation of mitochondrial hexokinase in cultured HT 29 human cancer cells. An ultrastructural and biochemical study. Biochim Biophys Acta. 1987 Sep 3;902(3):335–348. doi: 10.1016/0005-2736(87)90202-1. [DOI] [PubMed] [Google Scholar]
  14. Golshani-Hebroni S. G., Bessman S. P. Hexokinase binding to mitochondria: a basis for proliferative energy metabolism. J Bioenerg Biomembr. 1997 Aug;29(4):331–338. doi: 10.1023/a:1022442629543. [DOI] [PubMed] [Google Scholar]
  15. Gots R. E., Bessman S. P. The functional compartmentation of mitochondrial hexokinase. Arch Biochem Biophys. 1974 Jul;163(1):7–14. doi: 10.1016/0003-9861(74)90448-2. [DOI] [PubMed] [Google Scholar]
  16. Hackenbrock C. R. Chemical and physical fixation of isolated mitochondria in low-energy and high-energy states. Proc Natl Acad Sci U S A. 1968 Oct;61(2):598–605. doi: 10.1073/pnas.61.2.598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. IBSEN K. H. The Crabtree effect: a review. Cancer Res. 1961 Aug;21:829–841. [PubMed] [Google Scholar]
  19. Korzeniewski B., Mazat J. P. Theoretical studies on the control of oxidative phosphorylation in muscle mitochondria: application to mitochondrial deficiencies. Biochem J. 1996 Oct 1;319(Pt 1):143–148. doi: 10.1042/bj3190143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Laterveer F. D., Gellerich F. N., Nicolay K. Macromolecules increase the channeling of ADP from externally associated hexokinase to the matrix of mitochondria. Eur J Biochem. 1995 Sep 1;232(2):569–577. [PubMed] [Google Scholar]
  21. Lemeshko S. V., Lemeshko V. V. Metabolically derived potential on the outer membrane of mitochondria: a computational model. Biophys J. 2000 Dec;79(6):2785–2800. doi: 10.1016/S0006-3495(00)76518-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. 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]
  24. 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]
  25. Mathupala S. P., Rempel A., Pedersen P. L. Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase. J Bioenerg Biomembr. 1997 Aug;29(4):339–343. doi: 10.1023/a:1022494613613. [DOI] [PubMed] [Google Scholar]
  26. Mazurek S., Boschek C. B., Eigenbrodt E. The role of phosphometabolites in cell proliferation, energy metabolism, and tumor therapy. J Bioenerg Biomembr. 1997 Aug;29(4):315–330. doi: 10.1023/a:1022490512705. [DOI] [PubMed] [Google Scholar]
  27. Nakashima R. A., Paggi M. G., Scott L. J., Pedersen P. L. Purification and characterization of a bindable form of mitochondrial bound hexokinase from the highly glycolytic AS-30D rat hepatoma cell line. Cancer Res. 1988 Feb 15;48(4):913–919. [PubMed] [Google Scholar]
  28. Ohlendieck K., Riesinger I., Adams V., Krause J., Brdiczka D. Enrichment and biochemical characterization of boundary membrane contact sites from rat-liver mitochondria. Biochim Biophys Acta. 1986 Sep 11;860(3):672–689. doi: 10.1016/0005-2736(86)90567-5. [DOI] [PubMed] [Google Scholar]
  29. Pedersen P. L. Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res. 1978;22:190–274. doi: 10.1159/000401202. [DOI] [PubMed] [Google Scholar]
  30. Rodríguez-Enríquez S., Juárez O., Rodríguez-Zavala J. S., Moreno-Sánchez R. Multisite control of the Crabtree effect in ascites hepatoma cells. Eur J Biochem. 2001 Apr;268(8):2512–2519. doi: 10.1046/j.1432-1327.2001.02140.x. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. 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]
  33. Sandri G., Siagri M., Panfili E. Influence of Ca2+ on the isolation from rat brain mitochondria of a fraction enriched of boundary membrane contact sites. Cell Calcium. 1988 Aug;9(4):159–165. doi: 10.1016/0143-4160(88)90020-6. [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. Shinohara Y., Ishida T., Hino M., Yamazaki N., Baba Y., Terada H. Characterization of porin isoforms expressed in tumor cells. Eur J Biochem. 2000 Oct;267(19):6067–6073. doi: 10.1046/j.1432-1327.2000.01687.x. [DOI] [PubMed] [Google Scholar]
  36. Smith T. A. Mammalian hexokinases and their abnormal expression in cancer. Br J Biomed Sci. 2000;57(2):170–178. [PubMed] [Google Scholar]
  37. 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]
  38. Vander Heiden M. G., Li X. X., Gottleib E., Hill R. B., Thompson C. B., Colombini M. Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem. 2001 Mar 20;276(22):19414–19419. doi: 10.1074/jbc.M101590200. [DOI] [PubMed] [Google Scholar]
  39. WARBURG O. On the origin of cancer cells. Science. 1956 Feb 24;123(3191):309–314. doi: 10.1126/science.123.3191.309. [DOI] [PubMed] [Google Scholar]
  40. Weiler U., Riesinger I., Knoll G., Brdiczka D. The regulation of mitochondrial-bound hexokinases in the liver. Biochem Med. 1985 Apr;33(2):223–235. doi: 10.1016/0006-2944(85)90031-6. [DOI] [PubMed] [Google Scholar]
  41. Zalman L. S., Nikaido H., Kagawa Y. Mitochondrial outer membrane contains a protein producing nonspecific diffusion channels. J Biol Chem. 1980 Mar 10;255(5):1771–1774. [PubMed] [Google Scholar]
  42. Zoratti M., Szabò I. The mitochondrial permeability transition. Biochim Biophys Acta. 1995 Jul 17;1241(2):139–176. doi: 10.1016/0304-4157(95)00003-a. [DOI] [PubMed] [Google Scholar]

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