Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1991 Sep 15;278(Pt 3):715–719. doi: 10.1042/bj2780715

Calcium-dependent opening of a non-specific pore in the mitochondrial inner membrane is inhibited at pH values below 7. Implications for the protective effect of low pH against chemical and hypoxic cell damage.

A P Halestrap 1
PMCID: PMC1151405  PMID: 1654889

Abstract

1. The rate of opening of the Ca(2+)-induced non-specific, cyclosporin A-inhibited, pore of the mitochondrial inner membrane of rat heart and liver mitochondria at pH 6.0 was less than 10% of that at pH 7.4. 2. The effect could not be explained by inhibition of Ca2+ uptake into the mitochondria, or of the matrix peptidyl-prolyl cis-trans isomerase (PPIase), or of the Ca(2+)-induced conformational change of the adenine nucleotide translocase. 3. It is suggested that the proposed interaction of matrix PPIase with the 'c' conformation of the adenine nucleotide carrier in the presence of Ca2+ [Griffiths & Halestrap (1991) Biochem. J. 274, 611-614] is inhibited by low pH. 4. The relevance of this to the protective effect of low pH on hypoxic and chemical-induced cell damage is discussed.

Full text

PDF
717

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beatrice M. C., Stiers D. L., Pfeiffer D. R. The role of glutathione in the retention of Ca2+ by liver mitochondria. J Biol Chem. 1984 Jan 25;259(2):1279–1287. [PubMed] [Google Scholar]
  2. Bielecki K. The influence of changes in pH of the perfusion fluid on the occurrence of the calcium paradox in the isolated rat heart. Cardiovasc Res. 1969 Jul;3(3):268–271. doi: 10.1093/cvr/3.3.268. [DOI] [PubMed] [Google Scholar]
  3. Bonventre J. V., Cheung J. Y. Effects of metabolic acidosis on viability of cells exposed to anoxia. Am J Physiol. 1985 Jul;249(1 Pt 1):C149–C159. doi: 10.1152/ajpcell.1985.249.1.C149. [DOI] [PubMed] [Google Scholar]
  4. Broekemeier K. M., Dempsey M. E., Pfeiffer D. R. Cyclosporin A is a potent inhibitor of the inner membrane permeability transition in liver mitochondria. J Biol Chem. 1989 May 15;264(14):7826–7830. [PubMed] [Google Scholar]
  5. Broekemeier K. M., Pfeiffer D. R. Cyclosporin A-sensitive and insensitive mechanisms produce the permeability transition in mitochondria. Biochem Biophys Res Commun. 1989 Aug 30;163(1):561–566. doi: 10.1016/0006-291x(89)92174-8. [DOI] [PubMed] [Google Scholar]
  6. Crompton M., Costi A. A heart mitochondrial Ca2(+)-dependent pore of possible relevance to re-perfusion-induced injury. Evidence that ADP facilitates pore interconversion between the closed and open states. Biochem J. 1990 Feb 15;266(1):33–39. doi: 10.1042/bj2660033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Crompton M., Costi A. Kinetic evidence for a heart mitochondrial pore activated by Ca2+, inorganic phosphate and oxidative stress. A potential mechanism for mitochondrial dysfunction during cellular Ca2+ overload. Eur J Biochem. 1988 Dec 15;178(2):489–501. doi: 10.1111/j.1432-1033.1988.tb14475.x. [DOI] [PubMed] [Google Scholar]
  8. Crompton M., Ellinger H., Costi A. Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem J. 1988 Oct 1;255(1):357–360. [PMC free article] [PubMed] [Google Scholar]
  9. Currin R. T., Gores G. J., Thurman R. G., Lemasters J. J. Protection by acidotic pH against anoxic cell killing in perfused rat liver: evidence for a pH paradox. FASEB J. 1991 Feb;5(2):207–210. doi: 10.1096/fasebj.5.2.2004664. [DOI] [PubMed] [Google Scholar]
  10. Davidson A. M., Halestrap A. P. Liver mitochondrial pyrophosphate concentration is increased by Ca2+ and regulates the intramitochondrial volume and adenine nucleotide content. Biochem J. 1987 Sep 15;246(3):715–723. doi: 10.1042/bj2460715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Davidson A. M., Halestrap A. P. Partial inhibition by cyclosporin A of the swelling of liver mitochondria in vivo and in vitro induced by sub-micromolar [Ca2+], but not by butyrate. Evidence for two distinct swelling mechanisms. Biochem J. 1990 May 15;268(1):147–152. doi: 10.1042/bj2680147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dierks T., Salentin A., Heberger C., Krämer R. The mitochondrial aspartate/glutamate and ADP/ATP carrier switch from obligate counterexchange to unidirectional transport after modification by SH-reagents. Biochim Biophys Acta. 1990 Oct 19;1028(3):268–280. doi: 10.1016/0005-2736(90)90176-o. [DOI] [PubMed] [Google Scholar]
  13. Dierks T., Salentin A., Krämer R. Pore-like and carrier-like properties of the mitochondrial aspartate/glutamate carrier after modification by SH-reagents: evidence for a performed channel as a structural requirement of carrier-mediated transport. Biochim Biophys Acta. 1990 Oct 19;1028(3):281–288. doi: 10.1016/0005-2736(90)90177-p. [DOI] [PubMed] [Google Scholar]
  14. Fagian M. M., Pereira-da-Silva L., Martins I. S., Vercesi A. E. Membrane protein thiol cross-linking associated with the permeabilization of the inner mitochondrial membrane by Ca2+ plus prooxidants. J Biol Chem. 1990 Nov 15;265(32):19955–19960. [PubMed] [Google Scholar]
  15. Farber J. L., Chien K. R., Mittnacht S., Jr Myocardial ischemia: the pathogenesis of irreversible cell injury in ischemia. Am J Pathol. 1981 Feb;102(2):271–281. [PMC free article] [PubMed] [Google Scholar]
  16. Fry C. H., McGuigan J. A. The influence of pH on Ca2+ exchange in ferret heart mitochondria. Biochem Biophys Res Commun. 1990 Feb 14;166(3):1352–1357. doi: 10.1016/0006-291x(90)91015-k. [DOI] [PubMed] [Google Scholar]
  17. Gores G. J., Nieminen A. L., Fleishman K. E., Dawson T. L., Herman B., Lemasters J. J. Extracellular acidosis delays onset of cell death in ATP-depleted hepatocytes. Am J Physiol. 1988 Sep;255(3 Pt 1):C315–C322. doi: 10.1152/ajpcell.1988.255.3.C315. [DOI] [PubMed] [Google Scholar]
  18. Gores G. J., Nieminen A. L., Wray B. E., Herman B., Lemasters J. J. Intracellular pH during "chemical hypoxia" in cultured rat hepatocytes. Protection by intracellular acidosis against the onset of cell death. J Clin Invest. 1989 Feb;83(2):386–396. doi: 10.1172/JCI113896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Goto S., Kim Y. I., Kamada N., Kawano K., Kobayashi M. The beneficial effect of pretransplant cyclosporine therapy on recipient rats grafted with a 12-hour cold-stored liver. Transplantation. 1990 May;49(5):1003–1005. doi: 10.1097/00007890-199005000-00035. [DOI] [PubMed] [Google Scholar]
  20. Griffiths E. J., Halestrap A. P. Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. Implications for the immunosuppressive and toxic effects of cyclosporin. Biochem J. 1991 Mar 1;274(Pt 2):611–614. doi: 10.1042/bj2740611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gunter T. E., Pfeiffer D. R. Mechanisms by which mitochondria transport calcium. Am J Physiol. 1990 May;258(5 Pt 1):C755–C786. doi: 10.1152/ajpcell.1990.258.5.C755. [DOI] [PubMed] [Google Scholar]
  22. Halestrap A. P., Davidson A. M. Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem J. 1990 May 15;268(1):153–160. doi: 10.1042/bj2680153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Halestrap A. P., Poole R. C., Cranmer S. L. Mechanisms and regulation of lactate, pyruvate and ketone body transport across the plasma membrane of mammalian cells and their metabolic consequences. Biochem Soc Trans. 1990 Dec;18(6):1132–1135. doi: 10.1042/bst0181132. [DOI] [PubMed] [Google Scholar]
  24. Halestrap A. P. The regulation of the matrix volume of mammalian mitochondria in vivo and in vitro and its role in the control of mitochondrial metabolism. Biochim Biophys Acta. 1989 Mar 23;973(3):355–382. doi: 10.1016/s0005-2728(89)80378-0. [DOI] [PubMed] [Google Scholar]
  25. Halestrap A. P. The regulation of the oxidation of fatty acids and other substrates in rat heart mitochondria by changes in the matrix volume induced by osmotic strength, valinomycin and Ca2+. Biochem J. 1987 May 15;244(1):159–164. doi: 10.1042/bj2440159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Haworth R. A., Hunter D. R. The Ca2+-induced membrane transition in mitochondria. II. Nature of the Ca2+ trigger site. Arch Biochem Biophys. 1979 Jul;195(2):460–467. doi: 10.1016/0003-9861(79)90372-2. [DOI] [PubMed] [Google Scholar]
  27. Hayashi T., Nagasue N., Kohno H., Chang Y. C., Nakamura T. Beneficial effect of cyclosporine pretreatment in preventing ischemic damage to the liver in dogs. Transplantation. 1988 Dec;46(6):923–924. [PubMed] [Google Scholar]
  28. Herman B., Gores G. J., Nieminen A. L., Kawanishi T., Harman A., Lemasters J. J. Calcium and pH in anoxic and toxic injury. Crit Rev Toxicol. 1990;21(2):127–148. doi: 10.3109/10408449009089876. [DOI] [PubMed] [Google Scholar]
  29. Hunter D. R., Haworth R. A. The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. Arch Biochem Biophys. 1979 Jul;195(2):453–459. doi: 10.1016/0003-9861(79)90371-0. [DOI] [PubMed] [Google Scholar]
  30. Kawano K., Kim Y. I., Kaketani K., Kobayashi M. The beneficial effect of cyclosporine on liver ischemia in rats. Transplantation. 1989 Nov;48(5):759–764. doi: 10.1097/00007890-198911000-00007. [DOI] [PubMed] [Google Scholar]
  31. Kay J. E., Moore A. L., Doe S. E., Benzie C. R., Schönbrunner R., Schmid F. X., Halestrap A. P. The mechanism of action of FK 506. Transplant Proc. 1990 Feb;22(1):96–99. [PubMed] [Google Scholar]
  32. Kristensen S. R. A critical appraisal of the association between energy charge and cell damage. Biochim Biophys Acta. 1989 Aug 15;1012(3):272–278. doi: 10.1016/0167-4889(89)90108-0. [DOI] [PubMed] [Google Scholar]
  33. Lê Quôc K., Lê Quôc D. Involvement of the ADP/ATP carrier in calcium-induced perturbations of the mitochondrial inner membrane permeability: importance of the orientation of the nucleotide binding site. Arch Biochem Biophys. 1988 Sep;265(2):249–257. doi: 10.1016/0003-9861(88)90125-7. [DOI] [PubMed] [Google Scholar]
  34. Masaki N., Kyle M. E., Serroni A., Farber J. L. Mitochondrial damage as a mechanism of cell injury in the killing of cultured hepatocytes by tert-butyl hydroperoxide. Arch Biochem Biophys. 1989 May 1;270(2):672–680. doi: 10.1016/0003-9861(89)90550-x. [DOI] [PubMed] [Google Scholar]
  35. Masaki N., Thomas A. P., Hoek J. B., Farber J. L. Intracellular acidosis protects cultured hepatocytes from the toxic consequences of a loss of mitochondrial energization. Arch Biochem Biophys. 1989 Jul;272(1):152–161. doi: 10.1016/0003-9861(89)90206-3. [DOI] [PubMed] [Google Scholar]
  36. McCormack J. G., Browne H. M., Dawes N. J. Studies on mitochondrial Ca2+-transport and matrix Ca2+ using fura-2-loaded rat heart mitochondria. Biochim Biophys Acta. 1989 Mar 23;973(3):420–427. doi: 10.1016/s0005-2728(89)80384-6. [DOI] [PubMed] [Google Scholar]
  37. McCormack J. G., Halestrap A. P., Denton R. M. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev. 1990 Apr;70(2):391–425. doi: 10.1152/physrev.1990.70.2.391. [DOI] [PubMed] [Google Scholar]
  38. McGuinness O., Yafei N., Costi A., Crompton M. The presence of two classes of high-affinity cyclosporin A binding sites in mitochondria. Evidence that the minor component is involved in the opening of an inner-membrane Ca(2+)-dependent pore. Eur J Biochem. 1990 Dec 12;194(2):671–679. doi: 10.1111/j.1432-1033.1990.tb15667.x. [DOI] [PubMed] [Google Scholar]
  39. Miccadei S., Kyle M. E., Gilfor D., Farber J. L. Toxic consequence of the abrupt depletion of glutathione in cultured rat hepatocytes. Arch Biochem Biophys. 1988 Sep;265(2):311–320. doi: 10.1016/0003-9861(88)90133-6. [DOI] [PubMed] [Google Scholar]
  40. Moreno-Sánchez R., Hansford R. G. Dependence of cardiac mitochondrial pyruvate dehydrogenase activity on intramitochondrial free Ca2+ concentration. Biochem J. 1988 Dec 1;256(2):403–412. doi: 10.1042/bj2560403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Nieminen A. L., Dawson T. L., Gores G. J., Kawanishi T., Herman B., Lemasters J. J. Protection by acidotic pH and fructose against lethal injury to rat hepatocytes from mitochondrial inhibitors, ionophores and oxidant chemicals. Biochem Biophys Res Commun. 1990 Mar 16;167(2):600–606. doi: 10.1016/0006-291x(90)92067-a. [DOI] [PubMed] [Google Scholar]
  42. Olafsdottir K., Pascoe G. A., Reed D. J. Mitochondrial glutathione status during Ca2+ ionophore-induced injury to isolated hepatocytes. Arch Biochem Biophys. 1988 May 15;263(1):226–235. doi: 10.1016/0003-9861(88)90631-5. [DOI] [PubMed] [Google Scholar]
  43. Orrenius S., McConkey D. J., Bellomo G., Nicotera P. Role of Ca2+ in toxic cell killing. Trends Pharmacol Sci. 1989 Jul;10(7):281–285. doi: 10.1016/0165-6147(89)90029-1. [DOI] [PubMed] [Google Scholar]
  44. Penttila A., Trump B. F. Extracellular acidosis protects Ehrlich ascites tumor cells and rat renal cortex against anoxic injury. Science. 1974 Jul 19;185(4147):277–278. doi: 10.1126/science.185.4147.277. [DOI] [PubMed] [Google Scholar]
  45. Poole-Wilson P. A. Regulation of intracellular pH in the myocardium; relevance to pathology. Mol Cell Biochem. 1989 Sep 7;89(2):151–155. doi: 10.1007/BF00220768. [DOI] [PubMed] [Google Scholar]
  46. Steenbergen C., Murphy E., Watts J. A., London R. E. Correlation between cytosolic free calcium, contracture, ATP, and irreversible ischemic injury in perfused rat heart. Circ Res. 1990 Jan;66(1):135–146. doi: 10.1161/01.res.66.1.135. [DOI] [PubMed] [Google Scholar]
  47. Wan B., LaNoue K. F., Cheung J. Y., Scaduto R. C., Jr Regulation of citric acid cycle by calcium. J Biol Chem. 1989 Aug 15;264(23):13430–13439. [PubMed] [Google Scholar]
  48. Whipps D. E., Armston A. E., Pryor H. J., Halestrap A. P. Effects of glucagon and Ca2+ on the metabolism of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate in isolated rat hepatocytes and plasma membranes. Biochem J. 1987 Feb 1;241(3):835–845. doi: 10.1042/bj2410835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Zimmer G., Freisleben H. J., Fuchs J. Influence of pH on sulfhydryl groups and fluidity of the mitochondrial membrane. Arch Biochem Biophys. 1990 Nov 1;282(2):307–317. doi: 10.1016/0003-9861(90)90122-f. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES