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Basic Research in Cardiology

, Volume 88, Issue 5, pp 513–523 | Cite as

On the involvement of a mitochondrial pore in reperfusion injury

  • M. Crompton
  • L. Andreeva
Original Contributions

Summary

We review evidence implicating mitochondrial dysfunction in the pathogenesis of ischaemia/reperfusion injury. The lesion has been identified as a non selective pore that is triggered by Ca2+ and particular metabolic derangements associated with this form of injury, namely falling ATP, raised Pi and oxidative stress. Once activated, the pore flickers between open and closed states and disrupts mitochondrial energy transduction, allowing ATP hydrolysis by the FIFo ATPase. Pore activation is prevented by cyclosporin A, which also retards the onset of necrosis in heart cells subjected to substrate-free anoxia and allows partial regeneration of ATP on reoyxgenation.

Key words

Mitochondria Ca2+ reperfusion injury cyclosporin A 

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References

  1. 1.
    Adams V, Bosch W, Schlegel J, Wallinmann T, Brdliczka D (1989) Further characterisation of contact sites from mitochondria of different tissues. Biochem Biophys Acta 981:213–225Google Scholar
  2. 2.
    Allshire A, Piper MH, Cuthbertson KSR, Cobbold PA (1987) Cytosolic free Ca2+ in single rat heart cells during anoxia and reoxgenation. Biochem J 244:381–385Google Scholar
  3. 3.
    Al Nasser I, Crompton M (1986) The entrapment of the Ca2+ indicator arsenazo III in the matrix space of rat liver mitochondria by permeabilization and resealing. Biochem J 239:31–40Google Scholar
  4. 4.
    Awad M, Gavish M (1987) Binding of (3H)Ro 5-4864 and (3H) PK11195 to cerebral cortex and peripheral tissues of various species. J Neurochem 49:1407–1414Google Scholar
  5. 5.
    Benz R, Kottke M, Brdlizcka D (1990) The cationically selective state of the mitochondrial outer membrane pore. Biochem Biophys Acta 1022:311–318Google Scholar
  6. 6.
    Bernardi P (1992) Modulation of the mitochondrial cyclosporin A — sensitive permeability transition pore by the protein electrochemical gradient. J Biol Chem 267:8834–8839Google Scholar
  7. 7.
    Bowers K, Allshire AP, Cobbold PH (1992) Bioluminescent measurement in single cardiomyocytes of sudden cytosolic ATP depletion coincident with rigor. J Mol Cell Cardiol 24:211–216Google Scholar
  8. 8.
    Broderick R, Somlyo AP (1987) Calcium and magnesium transport by in situ mitochondria: Electron probe analysis of vascular smooth muscle. Circulation Res 61:523–530Google Scholar
  9. 9.
    Broekemeier K, Carpenter L, Reed DJ, Pfeiffer DR (1992) Cyclosporin A protects hepatocytes subjected to high Ca2+ and oxidative stress. FEBS Lett 304:192–194Google Scholar
  10. 10.
    Crompton M (1990) The role of Ca2+ in the function and dysfunction of heart mitochondria. In: Langer GA (ed) Calcium and the Heart. Raven Press, New York, pp 167–198Google Scholar
  11. 11.
    Crompton M, Costi A (1988) Kinetic evidence for a heart mitochondrial pore activated by Ca2+, inorganic phosphate and oxidative stress. Eur J Biochem 178:489–501Google Scholar
  12. 12.
    Crompton M, Costi A (1990) A heart mitochondrial pore of possible relevance to reperfusion-induced injury. Biochem J 226:33–39Google Scholar
  13. 13.
    Crompton M, Ellinger H, Costi A (1988) Inhibition by cyclosporin A of Ca2+ dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem J 255:257–360Google Scholar
  14. 14.
    Crompton M, McGuiness OM, Nazareth W (1992) The involvement of cyclosporin A binding proteins in regulating and uncoupling mitochondrial energy transduction. Biochem Biophys Acta 1101:214–217Google Scholar
  15. 15.
    Curello S, Ceconi C, Cagnoni A, Ferrari R, Albertini A (1987) Improved method for determination of glutathione as an index of myocardial oxidative stress. Clin Chem 33:1448–1449Google Scholar
  16. 16.
    Denton RM, McCormack JG (1985) Ca2+ transport by mammalian mitochondria and its role in hormone action. Am J Physiol 249:E543-E554Google Scholar
  17. 17.
    Duchen MR, McGuiness OM, Brown LA, Crompton M (1993) On the role of mitochondrial dysfunction in irreversible injury. Cardiovas Res, in pressGoogle Scholar
  18. 18.
    Ferrari R, DeLisa F, Raddino R, Visoli O (1982) The effects of ruthenium red on mitochondrial function during postischaemic reperfusion. J Mol Cell Cardiol 14:737–740Google Scholar
  19. 19.
    Ferrari R, Ceconi C, Carello S, Cagnoni A, Pasini E, De Giuli F, Albertini A (1991) Role of oxygen free radicals in ischaemic and reperfused myocardium. Am J Chem Nutr 53:2155–2225Google Scholar
  20. 20.
    Fournier N, Ducet G, Crevat A (1987) Action of cyclosporin on mitochondrial Ca2+ fluxes. J Bioenerg Biomembr 19:297–303Google Scholar
  21. 21.
    Garlick PB, Davies MJ, Hearse DJ, Slater TF (1987) Direct detection of free radicals in the reperfused rat heart using electron spin resonance spectroscopy. Circ Res 61:757–760Google Scholar
  22. 22.
    Halestrap AP, Davidson A (1990) Inhibition ov Ca2+-induced lare amplitude swelling by cyclosporin. Biochem J 268:153–160Google Scholar
  23. 23.
    Hansford RG (1991) Dehydrogenase activation by Ca2+ in cells and tissues. J Bioenerg Biomembr 23:823–854Google Scholar
  24. 24.
    Haworth RA, Hunter DR (1980) Allosteric inhibition of the Ca2+ activated hydrophilic channel of the mitochondrial inner membrane by nucleotides. J Membr Biol 54:231–236Google Scholar
  25. 25.
    Jennings RB, Steenbergen C (1985) Nucleotide metabolism and cellular damage in myocardial ischaemia. Ann Rev Physiol 47:727–749Google Scholar
  26. 26.
    Kass GEN, Juedes MJ, Orrenius S (1992) Cyclosporin A protects hepatocytes against prooxidant induced cell killing. Biochem Pharmacol 44:1995–2003Google Scholar
  27. 27.
    Kinally KW, Antonenko YN, Zoroo DB (1992) Hodalation of inner mitochondrial membrane channel activity. J Bioenerg Biomembr 24:99–109Google Scholar
  28. 28.
    Krishnamoorthy G, Hinkle PC (1988) Studies on the electron transfer pathway. Topography of Iron-Sulphur centres and site of coupling in NADH-Q oxidoreductase. J Biol Chem 263:17566–17575Google Scholar
  29. 29.
    Krueger KE, Papadopoulos V (1992) Mitochondrial benzodiazepine receptors and the regulation of steroid biosynthesis. Ann Rev Pharm Tox 32:211–237Google Scholar
  30. 30.
    LeFurgey A, Ingram P, Lieberman M (1988) Quantitative microchemical imaging of calcium in Na−K pump inhibited cells. Cell Calcium 9:219–235Google Scholar
  31. 31.
    LeQuoc K, LeQuoc D (1988) Involvement of the ADP/ATP carrier in calcium-induced perturbation of mitochondrial inner membrane permeability. Arch Biochem Biophys 265:249–257Google Scholar
  32. 32.
    McEnergy MW, Snowman AM, Trifiletti RR, Snyder SH (1992) Isolation of the mitochondrial benzodiazepine receptor. Association with the voltage dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci 89:3170–3174Google Scholar
  33. 33.
    McGuiness OM, Yafei N, Costi M, Crompton M (1990) The presence of two classes of high affinity cyclosporin A binding sites in mitochondria. Eur J Biochem 194:671–679Google Scholar
  34. 34.
    Masaki N, Thomas AP, Hoek JB, Farber JL (1989) Intracellular acidosis protects cultured hepatocytes from the toxic consequences of a loss of mitochondrial energization. Arch Biochem Biophys 272:152–161Google Scholar
  35. 35.
    Miyata H, Silvermann HS, Sollot SJ, Lakatta EG, Stern HD, Hansford RG (1991) Measurement of mitochondrial free Ca2+ concentration in living single rat cardiac myocytes. Am J Physiol 261:H1123-H1134Google Scholar
  36. 36.
    Moran O, Sandri G, Panfili E, Stuhmer W, Sorgato M (1990) Electrophysiological characterization of contact sites in brain mitochondria. J Biol Chem 265:908–913Google Scholar
  37. 37.
    Murphy E, Jacob R, Lieberman M (1985) Cytosolic free calcium in chick heart cells. J Mol Cell Cardiol 17:221–231Google Scholar
  38. 38.
    Nazareth W, Yafei N, Crompton M (1991) Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A. J Mol Cell Cardiol 23:1351–1354Google Scholar
  39. 39.
    Neckelmann N, Li K, Wade RP, Shuster R, Wallace DC (1987) cDNA sequence of a human skeletal muscle ADP/ATP translocater. Proc Natl Acad Sci (USA) 84:7580–7584Google Scholar
  40. 40.
    Nicholls DG, Brand MD (1980) The nature of the calcium ion efflux induced in mitochondria by the oxidation of endogenous nicotinannide nucleotides. Biochem J 188:113–118Google Scholar
  41. 41.
    Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 36:2503–2508Google Scholar
  42. 42.
    Nohl H, Jordan W (1984) In: Bors W, Saran M, Tati D (eds) Oxygen Radicals in Chemistry and Biology. Walter de Gruyter, Berlin, pp 155–160Google Scholar
  43. 43.
    Ono H, Tuboi S (1987) Integration of porin synthesized in vitro into outer mitochondrial membranes. Eur J Biochem 168:509–514Google Scholar
  44. 44.
    Peng C, Kane JS, Staub KD, Murphy ML (1980) Improvement of myocardial energy production in ischaemic myocardium by in vivo infusion of ruthenium Red. J Cardiovass. Pharmacol 2:45–54Google Scholar
  45. 45.
    Snyder JW, Pastorino JG, Attie AM, Farber JL (1992) Protection by cyclosporin A of cultured hepatocytes from the toxic consequences of the loss of mitochondrial energization produced by 1-methyl-4-phenylpyridinium. Biochem Pharmacol 44:833–835Google Scholar
  46. 46.
    Steenbergen C, Murphy E, Watts JA, London RE (1991) Correlation between cytosolic free calcium, contracture, ATP and irreversible ischaemic injury in perfused rat heart. Circ Res 66:135–146Google Scholar
  47. 47.
    Szabo I, Zoratti M (1992) The mitochondrial megachannel is the permeability transition pore. J Bioenerg Biomembr 24:111–117Google Scholar
  48. 48.
    Turrens JF, Boveris A (1980) Generation of superoxide anion by the NADH dehydrogenase of heart mitochondria. Biochem J 191:421–427Google Scholar
  49. 49.
    Zoccarato F, Rugolo M, Siliprandi D, Siliprandi N (1981) Correlated effluces of adenine nucleotides, Mg2+ and Ca2+ and phosphate. Eur J Biochem 114:195–199Google Scholar

Copyright information

© Steinkopff-Verlag 1993

Authors and Affiliations

  • M. Crompton
    • 1
  • L. Andreeva
    • 1
  1. 1.Department of Biochemistry & Molecular BiologyUniversity College LondonLondonUK

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