Mitochondria pp 291-301 | Cite as

The Role of Mitochondria in Necrosis Following Myocardial Ischemia-Reperfusion

  • Elizabeth Murphy
  • Charles Steenbergen
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 2)


Using the recently adopted nomenclature of cell death (Levin et al. 1999), necrosis refers to cell death and disintegration, regardless of the pathway; the modifiers apoptotic and oncotic are used to refer to the mechanism of death. Traditionally cell death following ischemia has been thought to be primarily oncotic necrosis. As detailed in numerous reviews, during ischemia when the ATP falls to very low levels, the ion pumps cannot function resulting in a rise in Ca2+ which further consumes ATP (Farber and Gerson 1984; Jennings et al. 1990; Jennings and Reimer 1981; Jennings and Steenbergen 1985). The rise in Ca2+ during ischemia and reperfusion leads to mitochondrial Ca2+ accumulation, particularly during reperfusion when oxygen is reintroduced. Reintroduction of oxygen provides a terminal electron acceptor (oxygen) allowing electron transport to occur; however damage to electron transport chain can lead to increased mitochondrial generation of reactive oxygen species (ROS).


Mitochondrial Membrane Potential Mitochondrial Permeability Transition Pore Voltage Dependent Anion Channel Adenine Nucleotide Translocator mPTP Opening 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Anversa P, Cheng W, Liu Y, Leri A, Redaelli G, Kajstura J (1998) Apoptosis and myocardial infarction. Basic Res Cardiol 93 Suppl 3: 8–12CrossRefGoogle Scholar
  2. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434: 658–662CrossRefPubMedGoogle Scholar
  3. Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y, Bolli R, Cardwell EM, Ping P (2003) Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res 92: 873–880CrossRefPubMedGoogle Scholar
  4. Baines CP, Zhang J, Wang GW, Zheng YT, Xiu JX, Cardwell EM, Bolli R, Ping P (2002) Mitochondrial PKCepsilon and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCepsilon-MAPK interactions and differential MAPK activation in PKCepsilon-induced cardioprotection. Circ Res 90: 390–397CrossRefPubMedGoogle Scholar
  5. Bartling B, Holtz J, Darmer D (1998) Contribution of myocyte apoptosis to myocardial infarction? Basic Res Cardiol 93: 71–84CrossRefPubMedGoogle Scholar
  6. Boengler K, Dodoni G, Rodriguez-Sinovas A, Cabestrero A, Ruiz-Meana M, Gres P, Konietzka I, Lopez-Iglesias C, Garcia-Dorado D, Di Lisa F, Heusch G, Schulz R (2005) Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc Res 67: 234–244CrossRefPubMedGoogle Scholar
  7. Chen Z, Chua CC, Ho YS, Hamdy RC, Chua BH (2001) Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol 280: H2313–2320PubMedGoogle Scholar
  8. Costa AD, Garlid KD, West IC, Lincoln TM, Downey JM, Cohen MV, Critz SD (2005) Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res 97: 329–336CrossRefPubMedGoogle Scholar
  9. Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302: 819–822CrossRefPubMedGoogle Scholar
  10. Di Lisa F, Bernardi P (1998) Mitochondrial function as a determinant of recovery or death in cell response to injury. Mol Cell Biochem 184: 379–391CrossRefPubMedGoogle Scholar
  11. Di Lisa F, Blank PS, Colonna R, Gambassi G, Silverman HS, Stern MD, Hansford RG (1995) Mitochondrial membrane potential in single living adult rat cardiac myocytes exposed to anoxia or metabolic inhibition. J Physiol 486 (pt 1): 1–13PubMedGoogle Scholar
  12. Farber JL, Gerson RJ (1984) Mechanisms of cell injury with hepatotoxic chemicals. Pharmacol Rev 36: 71S–75SPubMedGoogle Scholar
  13. Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D’Alonzo AJ, Lodge NJ, Smith MA, Grover GJ (1997) Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res 81: 1072–1082PubMedGoogle Scholar
  14. Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL (1994) Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 94: 1621–1628CrossRefPubMedGoogle Scholar
  15. Griffiths EJ, Halestrap AP (1993) Protection by Cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts. J Mol Cell Cardiol 25: 1461–1469CrossRefPubMedGoogle Scholar
  16. Halestrap A (2005) Biochemistry: a pore way to die. Nature 434: 578–579CrossRefPubMedGoogle Scholar
  17. Halestrap AP, Clarke SJ, Javadov SA (2004) Mitochondrial permeability transition pore opening during myocardial reperfusion–a target for cardioprotection. Cardiovasc Res 61: 372–385CrossRefPubMedGoogle Scholar
  18. Halestrap AP, Connern CP, Griffiths EJ, Kerr PM (1997) Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury. Mol Cell Biochem 174: 167–172CrossRefPubMedGoogle Scholar
  19. Hausenloy D, Wynne A, Duchen M, Yellon D (2004) Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation 109: 1714–1717CrossRefPubMedGoogle Scholar
  20. Imahashi K, Schneider MD, Steenbergen C, Murphy E (2004) Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ Res 95: 734–741CrossRefPubMedGoogle Scholar
  21. Jennings RB, Ganote CE (1976) Mitochondrial structure and function in acute myocardial ischemic injury. Circ Res 38: I80–91Google Scholar
  22. Jennings RB, Ganote CE (1976) Mitochondrial structure and function in acute myocardial ischemic injury. Circ Res 38: I80–91PubMedGoogle Scholar
  23. Jennings RB, Murry CE, Steenbergen C Jr, Reimer KA (1990) Development of cell injury in sustained acute ischemia. Circulation 82: II2–12PubMedGoogle Scholar
  24. Jennings RB, Reimer KA (1981) Lethal myocardial ischemic injury. Am J Pathol 102: 241–255PubMedGoogle Scholar
  25. Jennings RB, Steenbergen C Jr (1985) Nucleotide metabolism and cellular damage in myocardial ischemia. Annu Rev Physiol 47: 727–749CrossRefPubMedGoogle Scholar
  26. Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ (2004) Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 113: 1535–1549PubMedGoogle Scholar
  27. Karmazyn M (1988) Amiloride enhances postischemic ventricular recovery: possible role of Na+-H+ exchange. Am J Physiol 255: H608–615PubMedGoogle Scholar
  28. Kroemer G, Dallaporta B, Resche-Rigon M (1998) The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 60: 619–642CrossRefPubMedGoogle Scholar
  29. Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Mark W, Steurer W, Saks V, Usson Y, Margreiter R, Gnaiger E (2004) Mitochondrial defects and heterogeneous cytochrome c release after cardiac cold ischemia and reperfusion. Am J Physiol Heart Circ Physiol 286: H1633–1641CrossRefPubMedGoogle Scholar
  30. Levin S, Bucci TJ, Cohen SM, Fix AS, Hardisty JF, LeGrand EK, Maronpot RR, Trump BF (1999) The nomenclature of cell death: recommendations of an ad hoc Committee of the Society of Toxicologic Pathologists. Toxicol Pathol 27: 484–490CrossRefPubMedGoogle Scholar
  31. Leyssens A, Nowicky AV, Patterson L, Crompton M, Duchen MR (1996) The relationship between mitochondrial state, ATP hydrolysis, [Mg2+]i and [Ca2+]i studied in isolated rat cardiomyocytes. J Physiol 496 (Pt 1): 111–128PubMedGoogle Scholar
  32. Maloyan A, Sanbe A, Osinska H, Westfall M, Robinson D, Imahashi K, Murphy E, Robbins J (2005) Mitochondrial dysfunction and apoptosis underlie the pathogenic process in alpha-B-crystallin desmin-related cardiomyopathy. Circulation 112: 3451–3461CrossRefPubMedGoogle Scholar
  33. Murphy E, Perlman M, London RE, Steenbergen C (1991) Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res 68: 1250–1258PubMedGoogle Scholar
  34. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434: 652–658CrossRefPubMedGoogle Scholar
  35. O’Rourke B (2004) Evidence for mitochondrial K+ channels and their role in cardioprotection. Circ Res 94: 420–432CrossRefPubMedGoogle Scholar
  36. Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Federici A, Ruggiero FM (2004) Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart: involvement of reactive oxygen species and cardiolipin. Circ Res 94: 53–59CrossRefPubMedGoogle Scholar
  37. Rodriguez M, Schaper J (2005) Apoptosis: measurement and technical issues. J Mol Cell Cardiol 38: 15–20CrossRefPubMedGoogle Scholar
  38. Rouslin W, Broge CW (1996) IF1 function in situ in uncoupler-challenged ischemic rabbit, rat, and pigeon hearts. J Biol Chem 271: 23638–23641CrossRefPubMedGoogle Scholar
  39. Schneider MD (2005) Cyclophilin D: knocking on death’s door. Sci STKE 2005 pe26Google Scholar
  40. Shiraishi J, Tatsumi T, Keira N, Akashi K, Mano A, Yamanaka S, Matoba S, Asayama J, Yaoi T, Fushiki S, Fliss H, Nakagawa M (2001) Important role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis. Am J Physiol Heart Circ Physiol 281: H1637–1647PubMedGoogle Scholar
  41. Steenbergen C, Murphy E, Levy L, London RE (1987) Elevation in cytosolic free calcium concentration early in myocardial ischemia in perfused rat heart. Circ Res 60: 700–707PubMedGoogle Scholar
  42. Steenbergen C, Murphy E, Watts JA, London RE (1990) Correlation between cytosolic free calcium, contracture, ATP, and irreversible ischemic injury in perfused rat heart. Circ Res 66: 135–146PubMedGoogle Scholar
  43. Zamzami N, Larochette N, Kroemer G (2005) Mitochondrial permeability transition in apoptosis and necrosis. Cell Death Differ 12 Suppl 2: 1478–1480CrossRefGoogle Scholar
  44. Zhu L, Yu Y, Chua BH, Ho YS, Kuo TH (2001) Regulation of sodium-calcium exchange and mitochondrial energetics by Bcl-2 in the heart of transgenic mice. J Mol Cell Cardiol 33: 2135–2144CrossRefPubMedGoogle Scholar
  45. Zong WX, Thompson CB (2006) Necrotic death as a cell fate. Genes Dev 20: 1–15CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Elizabeth Murphy
  • Charles Steenbergen

There are no affiliations available

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