Skip to main content

Advertisement

SpringerLink
Log in

The Mitochondrial Permeability Transition Pore and the Cardiac Necrotic Program

  • Riley Symposium
  • Published:
Pediatric Cardiology Aims and scope Submit manuscript

Abstract

That apoptosis is mediated by specific pathways has long been established. However, more recent data have begun to suggest that necrosis may in fact be “programmed” and not a default “accidental” pathway as previously thought. The mitochondrial permeability transition pore, a known contributor to the development of many cardiac diseases, is emerging as one among several mediators of this necrotic program. Consequently, this report briefly reviews the roles of necrosis versus apoptosis in the pathogenesis of cardiac disease and discusses the role that the mitochondrial pore plays in cardiac necrotic cell death.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Akula A, Kota MK, Gopisetty SG, Chitrapu RV, Kalagara M, Kalagara S, Veeravalli KK, Gomedhikam JP (2003) Biochemical, histological, and echocardiographic changes during experimental cardiomyopathy in STZ-induced diabetic rats. Pharmacol Res 48:429–435

    Article  PubMed  CAS  Google Scholar 

  2. Baines CP (2010) The cardiac mitochondrion: nexus of stress. Annu Rev Physiol 72:61–80

    Article  PubMed  CAS  Google Scholar 

  3. 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 434:658–662

    Article  PubMed  CAS  Google Scholar 

  4. Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD (2007) Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol 9:550–555

    Article  PubMed  CAS  Google Scholar 

  5. Bialik S, Geenen DL, Sasson IE, Cheng R, Horner JW, Evans SM, Lord EM, Koch CJ, Kitsis RN (1997) Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53. J Clin Invest 100:1363–1372

    Article  PubMed  CAS  Google Scholar 

  6. Bisognano JD, Weinberger HD, Bohlmeyer TJ, Pende A, Raynolds MV, Sastravaha A, Roden R, Asano K, Blaxall BC, Wu SC, Communal C, Singh K, Colucci W, Bristow MR, Port DJ (2000) Myocardial-directed overexpression of the human b1-adrenergic receptor in transgenic mice. J Mol Cell Cardiol 32:817–830

    Article  PubMed  CAS  Google Scholar 

  7. Bonventre JV, Weinberg JM (2003) Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol 14:2199–2210

    Article  PubMed  Google Scholar 

  8. Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA (2007) AIF-mediated programmed necrosis: a highly regulated way to die. Cell Cycle 6:2612–2619

    Article  PubMed  CAS  Google Scholar 

  9. Buja LM (2005) Myocardial ischemia and reperfusion injury. Cardiovasc Pathol 14:170–175

    Article  PubMed  CAS  Google Scholar 

  10. Chen Y, Lewis W, Diwan A, Cheng EH, Matkovich SJ, Dorn GW (2010) Dual autonomous mitochondrial cell death pathways are activated by Nix/BNip3L and induce cardiomyopathy. Proc Natl Acad Sci USA 107:9035–9042

    Article  PubMed  CAS  Google Scholar 

  11. Clarke SJ, McStay GP, Halestrap AP (2002) Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A. J Biol Chem 277:34793–34799

    Article  PubMed  CAS  Google Scholar 

  12. Di Lisa F, Menabò R, Canton M, Barile M, Bernardi P (2001) Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J Biol Chem 276:2571–2575

    Article  PubMed  CAS  Google Scholar 

  13. Diwan A, Matkovich SJ, Yuan Q, Zhao W, Yatani A, Brown JH, Molkentin JD, Kranias EG, Dorn GW (2009) Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death. J Clin Invest 119:203–212

    PubMed  CAS  Google Scholar 

  14. Duchen MR, McGuinness O, Brown LA, Crompton M (1993) On the involvement of a cyclosporin A sensitive mitochondrial pore in myocardial reperfusion injury. Cardiovasc Res 27:1790–1794

    Article  PubMed  CAS  Google Scholar 

  15. Durbeej M, Cohn RD, Hrstka RF, Moore SA, Allamand V, Davidson BL, Williamson RA, Campbell KP (2000) Disruption of the β-sarcoglycan gene reveals pathogenetic complexity of limb-girdle muscular dystrophy type 2E. Mol Cell 5:141–151

    Article  PubMed  CAS  Google Scholar 

  16. Fein FS, Cho S, Zola BE, Miller B, Factor SM (1989) Cardiac pathology in the hypertensive diabetic rat: biventricular damage with right ventricular predominance. Am J Pathol 134:1159–1166

    PubMed  CAS  Google Scholar 

  17. Garcia JH, Anderson ML (1989) Physiopathology of cerebral ischemia. Crit Rev Neurobiol 4:303–324

    PubMed  CAS  Google Scholar 

  18. Geng YJ, Ishikawa Y, Vatner DE, Wagner TE, Bishop SP, Vatner SF, Homcy CJ (1999) Apoptosis of cardiac myocytes in Gsa transgenic mice. Circ Res 84:34–42

    PubMed  CAS  Google Scholar 

  19. Griffiths EJ, Halestrap AP (1993) Protection by cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts. J Mol Cell Cardiol 25:1461–1469

    Article  PubMed  CAS  Google Scholar 

  20. Gottlieb RA, Mentzer RM (2010) Autophagy during cardiac stress: joys and frustrations of autophagy. Annu Rev Physiol 72:45–59

    Article  PubMed  CAS  Google Scholar 

  21. Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiol 46:821–831

    Article  PubMed  CAS  Google Scholar 

  22. Hausenloy DJ, Duchen MR, Yellon DM (2003) Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia–reperfusion injury. Cardiovasc Res 60:617–625

    Article  PubMed  CAS  Google Scholar 

  23. Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, Yuan J (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135:1311–1323

    Article  PubMed  CAS  Google Scholar 

  24. Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, Van Etten RA, Alroy J, Durand JB, Force T (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908–916

    Article  PubMed  Google Scholar 

  25. Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465

    Article  PubMed  CAS  Google Scholar 

  26. Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163

    Article  PubMed  CAS  Google Scholar 

  27. Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G, Nomenclature Committee on Cell Death 2009 (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 16:3–11

    Article  PubMed  CAS  Google Scholar 

  28. Li X, Klaus JA, Zhang J, Xu Z, Kibler KK, Andrabi SA, Rao K, Yang ZJ, Dawson TM, Dawson VL, Koehler RC (2010) Contributions of poly(ADP-ribose) polymerase-1 and -2 to nuclear translocation of apoptosis-inducing factor and injury from focal cerebral ischemia. J Neurochem 113:1012–1022

    Article  PubMed  CAS  Google Scholar 

  29. Lim SY, Davidson SM, Mocanu MM, Yellon DM, Smith CC (2007) The cardioprotective effect of necrostatin requires the cyclophilin-D component of the mitochondrial permeability transition pore. Cardiovasc Drugs Ther 21:467–469

    Article  PubMed  CAS  Google Scholar 

  30. Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M, Eppenberger HM, Suter TM, Liao R, Sawyer DB (2004) Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem 279:8290–8299

    Article  PubMed  CAS  Google Scholar 

  31. 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 αB-crystallin desmin-related cardiomyopathy. Circulation 112:3451–3461

    Article  PubMed  CAS  Google Scholar 

  32. Matsumura K, Campbell KP (1993) Deficiency of dystrophin-associated proteins: a common mechanism leading to muscle cell necrosis in severe childhood muscular dystrophies. Neuromuscul Disord 3:109–118

    Article  PubMed  CAS  Google Scholar 

  33. Millay DP, Sargent MA, Osinska H, Baines CP, Barton ER, Vuagniaux G, Sweeney HL, Robbins J, Molkentin JD (2008) Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nat Med 14:442–447

    Article  PubMed  CAS  Google Scholar 

  34. Milner DJ, Weitzer G, Tran D, Bradley A, Capetanaki Y (1996) Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. J Cell Biol 134:1255–1270

    Article  PubMed  CAS  Google Scholar 

  35. Moquin D, Chan FK (2010) The molecular regulation of programmed necrotic cell injury. Trends Biochem Sci 35:434–441

    Article  PubMed  CAS  Google Scholar 

  36. Morgan MJ, Kim YS, Liu ZG (2008) TNFα and reactive oxygen species in necrotic cell death. Cell Res 18:343–349

    Article  PubMed  CAS  Google Scholar 

  37. 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 434:652–658

    Article  PubMed  CAS  Google Scholar 

  38. Nakayama H, Chen X, Baines CP, Klevitsky R, Zhang X, Zhang H, Jaleel N, Chua BH, Hewett TE, Robbins J, Houser SR, Molkentin JD (2007) Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin Invest 117:2431–2444

    Article  PubMed  CAS  Google Scholar 

  39. Okada K, Minamino T, Tsukamoto Y, Liao Y, Tsukamoto O, Takashima S, Hirata A, Fujita M, Nagamachi Y, Nakatani T, Yutani C, Ozawa K, Ogawa S, Tomoike H, Hori M, Kitakaze M (2004) Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110:705–712

    Article  PubMed  Google Scholar 

  40. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M (2008) Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 359:473–481

    Article  PubMed  CAS  Google Scholar 

  41. Reimer KA, Jennings RB (1979) The “wavefront phenomenon” of myocardial ischemic cell death: II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest 40:633–644

    PubMed  CAS  Google Scholar 

  42. Saito S, Hiroi Y, Zou Y, Aikawa R, Toko H, Shibasaki F, Yazaki Y, Nagai R, Komuro I (2000) β-Adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes. J Biol Chem 275:34528–34533

    Article  PubMed  CAS  Google Scholar 

  43. Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, Hetz C, Danial NN, Moskowitz MA, Korsmeyer SJ (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci USA 102:12005–12010

    Article  PubMed  CAS  Google Scholar 

  44. Singal PK, Li T, Kumar D, Danelisen I, Iliskovic N (2000) Adriamycin-induced heart failure: mechanism and modulation. Mol Cell Biochem 207:77–86

    Article  PubMed  CAS  Google Scholar 

  45. Vandenabeele P, Vanden Berghe T, Festjens N (2006) Caspase inhibitors promote alternative cell death pathways. Sci STKE 358:pe44

    Article  Google Scholar 

  46. Vandenabeele P, Declercq W, Van Herreweghe F, Vanden Berghe T (2010) The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. Sci Signal 3:re4

    Article  PubMed  Google Scholar 

  47. Wang Y, Kim NS, Li X, Greer PA, Koehler RC, Dawson VL, Dawson TM (2009) Calpain activation is not required for AIF translocation in PARP-1-dependent cell death (parthanatos). J Neurochem 110:687–696

    Article  PubMed  CAS  Google Scholar 

  48. Welch S, Plank D, Witt S, Glascock B, Schaefer E, Chimenti S, Andreoli AM, Limana F, Leri A, Kajstura J, Anversa P, Sussman MA (2002) Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. Circ Res 90:641–648

    Article  PubMed  CAS  Google Scholar 

  49. Xu Y, Huang S, Liu ZG, Han J (2006) Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. J Biol Chem 281:8788–8795

    Article  PubMed  CAS  Google Scholar 

  50. Yamaguchi O, Watanabe T, Nishida K, Kashiwase K, Higuchi Y, Takeda T, Hikoso S, Hirotani S, Asahi M, Taniike M, Nakai A, Tsujimoto I, Matsumura Y, Miyazaki J, Chien KR, Matsuzawa A, Sadamitsu C, Ichijo H, Baccarini M, Hori M, Otsu K (2004) Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J Clin Invest 114:937–943

    PubMed  CAS  Google Scholar 

  51. Yaoita H, Ogawa K, Maehara K, Maruyama Y (1998) Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation 97:276–281

    PubMed  CAS  Google Scholar 

  52. Zhang D, Gaussin V, Taffet GE, Belaguli NS, Yamada M, Schwartz RJ, Michael LH, Overbeek PA, Schneider MD (2000) TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nat Med 6:556–563

    Article  PubMed  CAS  Google Scholar 

  53. Zong WX, Thompson CB (2006) Necrotic death as a cell fate. Genes Dev 20:1–15

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, Dalton Cardiovascular Research Center, University of Missouri-Columbia, 134 Research Park Drive, Columbia, MO, 65211, USA

    Christopher P. Baines

  2. Department of Medical Pharmacology and Physiology, Dalton Cardiovascular Research Center, University of Missouri-Columbia, 134 Research Park Drive, Columbia, MO, 65211, USA

    Christopher P. Baines

Authors
  1. Christopher P. Baines
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher P. Baines.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baines, C.P. The Mitochondrial Permeability Transition Pore and the Cardiac Necrotic Program. Pediatr Cardiol 32, 258–262 (2011). https://doi.org/10.1007/s00246-010-9880-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00246-010-9880-9

Keywords

Search

Navigation