Cardiovascular Drugs and Therapy

, Volume 20, Issue 6, pp 425–432 | Cite as

Mitochondrial Permeability Transition in Cardiac Cell Injury and Death

Review

Abstract

Mitochondria can serve as the arbiter of cell fate in response to stress. Mitochondrial permeability transition (MPT) is characterized by permeabilization of an otherwise relatively impermeable mitochondrial inner membrane and appears to have a major role in ischemia/reperfusion (I/R) injury in myocardial infarction and stroke. After I/R, the fate of the cell is determined by the extent of MPT. If minimal, the cell may recover; if moderate, the cell may undergo programmed cell death; if severe, the cell may die from necrosis due to inadequate energy production. After reviewing the role of MPT in disease, we examine the signaling and metabolic networks that regulate MPT. We then conclude with some of the challenges in future MPT research.

Key words

mitochondrial permeability transition proteomics signaling networks metabolism 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Appaix F, Guerrero K, Rampal D, Izikki M, Kaambre T, Sikk P, et al. Bax and heart mitochondria: uncoupling and inhibition of respiration without permeability transition. Biochim Biophys Acta 2002;1556 2–3:155–67.PubMedGoogle Scholar
  2. 2.
    Ardehali H, Chen Z, Ko Y, Mejía-Alvarez R, Marbán E. Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity. Proc Natl Acad Sci U S A 2004;101 32:11880–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M. Postconditioning inhibits mitochondrial permeability transition. Circulation 2005;111 2:194–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Atan Gross JMM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev 2006;13:1899–911.Google Scholar
  5. 5.
    Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V. In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death. Biochem J 2004;377 Pt 2:347–55.PubMedCrossRefGoogle Scholar
  6. 6.
    Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005;434 7033:658–62.PubMedCrossRefGoogle Scholar
  7. 7.
    Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, et al. Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res 2003;92 8:873–80.PubMedCrossRefGoogle Scholar
  8. 8.
    Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P. Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 2005;280 19:18558–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Bathori G, Csordas G, Garcia-Perez C, Davies E Hajnoczky G. Ca2+-dependent control of the permeability properties of the mitochondrial outer membrane and VDAC. J Biol Chem 2006;281:17347–58.PubMedCrossRefGoogle Scholar
  10. 10.
    Boldogh IR, Pon LA. Interactions of mitochondria with the actin cytoskeleton. Biochim Biophys Acta 2006;1763 5–6:450–62.PubMedGoogle Scholar
  11. 11.
    Brookes PS, Darley-Usmar VM. Role of calcium and superoxide dismutase in sensitizing mitochondria to peroxynitrite-induced permeability transition. Am J Physiol Heart Circ Physiol 2004;286 1:H39-46.PubMedCrossRefGoogle Scholar
  12. 12.
    Brookes PS, Kraus DW, Shiva S, Doeller JE, Barone MC, Patel RP, et al. Control of mitochondrial respiration by NO*, effects of low oxygen and respiratory state. J Biol Chem 2003;278 34:31603–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Brustovetsky N, Klingenberg M. Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+. Biochemistry 1996;35 26:8483–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Chen L, Hahn H, Wu G, Chen C-H, Liron T, Schechtman D, et al. Opposing cardioprotective actions and parallel hypertrophic effects of delta PKC and epsilon PKC. Proc Natl Acad Sci U S A 2001;98 20:11114–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen M, Gan H, Remold HG. A mechanism of virulence: virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis. J Immunol 2006;176 6:3707–16.PubMedGoogle Scholar
  16. 16.
    Chen Z, Chua CC, Ho Y-S, Hamdy RC, Chua BHL. Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol 2001;280 5:H2313–20.PubMedGoogle Scholar
  17. 17.
    Chua, BT, Volbracht C, Tan K, Li R, Yu VC, Li P. Mitochondrial translocation of cofilin is an early step in apoptosis induction. Nat Cell Biol 2003;5 12:1083–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Churchill EN, Szweda LI. Translocation of deltaPKC to mitochondria during cardiac reperfusion enhances superoxide anion production and induces loss in mitochondrial function. Arch Biochem Biophys 2005;439 2:194–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Costa AD, Garlid KD, West IC, Lincoln TM, Downey JM, Cohen MV, et al. Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res 2005;97 4:329–36.PubMedCrossRefGoogle Scholar
  20. 20.
    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;245 3:915–8.PubMedGoogle Scholar
  21. 21.
    Denton RM, McCormack JG, Edyell NJ. Role of calcium ions in the regulation of intramitochondrial metabolism. Effects of Na+, Mg2+ and ruthenium red on the Ca2+-stimulated oxidation of oxoglutarate and on pyruvate dehydrogenase activity in intact rat heart mitochondria. Biochem J 1980;190 1:107–17.PubMedGoogle Scholar
  22. 22.
    Epand RF, Martinou JC, Fornallaz-Muhauser M, Hughes DW, Epand RM. The apoptotic protein tBid promotes leakage by altering membrane curvature. J Biol Chem 2002;277 36:32632–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol 2000;2 3:156–62.PubMedCrossRefGoogle Scholar
  24. 24.
    Griffiths EJ, Halestrap AP. Protection by Cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts. J Mol Cell Cardiol 1993;25 12:1461–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Griffiths EJ, Halestrap AP. Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J 1995;307 Pt 1:93–8.PubMedGoogle Scholar
  26. 26.
    Gunter TE, Yule DI, Gunter KK, Eliseev RA, Salter JD. Calcium and mitochondria. FEBS Lett 2004;567 1:96–102.PubMedCrossRefGoogle Scholar
  27. 27.
    Halestrap AP. Mitochondrial permeability: dual role for the ADP/ATP translocator? Nature 2004;430 7003:1–983.PubMedCrossRefGoogle Scholar
  28. 28.
    Harman D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol 1956;11.Google Scholar
  29. 29.
    Hausenloy DJ, Yellon DM, Mani-Babu S, Duchen MR. Preconditioning protects by inhibiting the mitochondrial permeability transition. Am J Physiol Heart Circ Physiol 2004;287 2:H841–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Haworth RA, Hunter DR. The Ca2+-induced membrane transition in mitochondria. II. Nature of the Ca2+ trigger site. Arch Biochem Biophys 1979;195 2:460–7.PubMedCrossRefGoogle Scholar
  31. 31.
    He L, Lemasters JJ. Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function? FEBS Lett 2002;512 1–3:1–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Hunter DR, Haworth RA. The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. Arch Biochem Biophys 1979;195 2:453–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Hunter DR, Haworth RA. The Ca2+-induced membrane transition in mitochondria. III. Transitional Ca2+ release. Arch Biochem Biophys 1979;195 2:468–77.PubMedCrossRefGoogle Scholar
  34. 34.
    Ichas F, Mazat JP. From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state. Biochim Biophys Acta 1998;1366 1–2:33–50.PubMedGoogle Scholar
  35. 35.
    Imahashi K, Schneider MD, Steenbergen C, Murphy E. Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ Res 2004;95 7:734–41.PubMedCrossRefGoogle Scholar
  36. 36.
    IONA. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet 2002;359 9314:1269–75.CrossRefGoogle Scholar
  37. 37.
    Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP. Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol 2003;549 Pt 2:513–24.PubMedCrossRefGoogle Scholar
  38. 38.
    Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, et al. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 2004;113 11:1535–49.PubMedCrossRefGoogle Scholar
  39. 39.
    Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation 2001;104 24:2981–9.PubMedGoogle Scholar
  40. 40.
    Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 2004;427 6973:461–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Korge P, Honda HM, Weiss JN. Protection of cardiac mitochondria by diazoxide and protein kinase C: implications for ischemic preconditioning. Proc Natl Acad Sci U S A 2002;99 5:3312–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Korge P, Honda HM, Weiss JN. Effects of fatty acids in isolated mitochondria: implications for ischemic injury and cardioprotection. Am J Physiol Heart Circ Physiol 2003;285 1:H259–69.PubMedGoogle Scholar
  43. 43.
    Kottke M, Adam V, Riesinger I, Bremm G, Bosch W, Brdiczka D, et al. Mitochondrial boundary membrane contact sites in brain: points of hexokinase and creatine kinase location, and control of Ca2+ transport. Biochim Biophys Acta 1988;935 1:87–102.PubMedCrossRefGoogle Scholar
  44. 44.
    Kowaltowski AJ, Fenton RG, Fiskum G. Bcl-2 family proteins regulate mitochondrial reactive oxygen production and protect against oxidative stress. Free Radic Biol Med 2004;37 11:1845–53.PubMedCrossRefGoogle Scholar
  45. 45.
    Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, et al. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 2002;111 3:331–42.PubMedCrossRefGoogle Scholar
  46. 46.
    Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 2004;16 5:819–30.PubMedCrossRefGoogle Scholar
  47. 47.
    Manfredi G, Kwong JQ, Oca-Cossio JA, Woischnik M, Gajewski CD, Martushova K, et al. BCL-2 improves oxidative phosphorylation and modulates adenine nucleotide translocation in mitochondria of cells harboring mutant mtDNA. J Biol Chem 2003;278 8:5639–45.PubMedCrossRefGoogle Scholar
  48. 48.
    Massari S. Kinetic analysis of the mitochondrial permeability transition. J Biol Chem 1996;271 50:31942–8.PubMedGoogle Scholar
  49. 49.
    Montero M, Lobaton CD, Gutierrez-Fernandez S, Moreno A, Alvarez J. Calcineurin-independent inhibition of mitochondrial Ca2+ uptake by cyclosporin A. Br J Pharmacol 2004;141 2:263–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Murphy AN, Bredesen DE, Cortopassi G, Wang E, Fiskum G. Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc Natl Acad Sci U S A 1996;93 18:9893–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74 5:1124–36.PubMedGoogle Scholar
  52. 52.
    Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 2005;434 7033:652–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Nazareth W, Yafei N, Crompton M. Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A. J Mol Cell Cardiol 1991;23 12:1351–4.PubMedCrossRefGoogle Scholar
  54. 54.
    Pastorino JG, Hoek JB, Shulga N. Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 2005;65 22:10545–54.PubMedCrossRefGoogle Scholar
  55. 55.
    Pastorino JG, Tafani M, Rothman RJ, Marcinkeviciute A, Hoek JB, Farber JL, et al. Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J Biol Chem 1999;274 44:31734–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Sato T, Sasaki N, Seharaseyon J, O’Rourke B, Marban E. Selective pharmacological agents implicate mitochondrial but not sarcolemmal K(ATP) channels in ischemic cardioprotection. Circulation 2000;101 20:2418–23.PubMedGoogle Scholar
  57. 57.
    Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, et al. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A 2005;102 34:12005–10.PubMedCrossRefGoogle Scholar
  58. 58.
    Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA, et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2002;2 1:55–67.PubMedCrossRefGoogle Scholar
  59. 59.
    Shimizu S, Eguchi Y, Kamiike W, Funahashi Y, Mignon A, Lacronique V, et al. Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux. Proc Natl Acad Sci U S A 1998;95 4:1455–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Skulachev VP. Why are mitochondria involved in apoptosis? Permeability transition pores and apoptosis as selective mechanisms to eliminate superoxide-producing mitochondria and cell. FEBS Lett 1996;397 1:7–10.PubMedCrossRefGoogle Scholar
  61. 61.
    Szabo I, Zoratti M. The giant channel of the inner mitochondrial membrane is inhibited by cyclosporin A. J Biol Chem 1991;266 6:3376–9.PubMedGoogle Scholar
  62. 62.
    Tang HL, Le AH, Lung HL. The increase in mitochondrial association with actin precedes Bax translocation in apoptosis. Biochem J 2006;396 1:1–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Weiss, JN Korge P, Honda HM, Ping P. Role of the mitochondrial permeability transition in myocardial disease. Circ Res 2003;93 4:292–301.PubMedCrossRefGoogle Scholar
  64. 64.
    Xu W, Liu Y, Wang S, McDonald T, Van Eyk JE, Sidor A, et al. Cytoprotective role of Ca2+-activated K+ channels in the cardiac inner mitochondrial membrane. Science 2002;298 5595:1029–33.PubMedCrossRefGoogle Scholar
  65. 65.
    Zamarin D, Garcia-Sastre A, Xiao X, Wang R, Palese P. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog 2005;1 1:e4.PubMedCrossRefGoogle Scholar
  66. 66.
    Zamzami N, Kroemer G. The mitochondrion in apoptosis: how Pandora’s box opens. Nat Rev Mol Cell Biol 2001;2 1:67–71.PubMedCrossRefGoogle Scholar
  67. 67.
    Zamzami N, Maisse C, Metivier D, Kroemer G. Measurement of membrane permeability and permeability transition of mitochondria. Methods Cell Biol 2001;65:147–58.PubMedCrossRefGoogle Scholar
  68. 68.
    Zoratti M, Szabo I, De Marchi U. Mitochondrial permeability transitions: how many doors to the house? Biochim Biophys Acta 2005;1706 1–2:40–52.PubMedGoogle Scholar
  69. 69.
    Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ. Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 2000;192 7:1001–14.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  1. 1.Department of MedicineDavid Geffen School of Medicine at the University of CaliforniaLos AngelesUSA
  2. 2.Department of Physiology and MedicineDavid Geffen School of Medicine at the University of CaliforniaLos AngelesUSA

Personalised recommendations