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Basic Research in Cardiology
Published in: Basic Research in Cardiology 2/2009

01-03-2009 | Review

The mitochondrial permeability transition pore and ischemia-reperfusion injury

Author: Christopher P. Baines

Published in: Basic Research in Cardiology | Issue 2/2009

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Abstract

Mitochondrial dysfunction is an underlying cause of ischemia-reperfusion injury. In particular, ischemic injury induces dramatic increases in mitochondrial permeability, thereby instigating a chain of events that leads to both apoptotic and necrotic cardiomyocyte death. The mitochondrial permeability transition (MPT) pore, a large, non-specific channel that spans the inner mitochondrial membrane, is known to mediate the lethal permeability changes that initiate mitochondrial-driven cardiomyocyte death. The purpose of this review is to focus on the role of the MPT pore in ischemia-reperfusion injury, the mechanisms involved, and, in particular, what we do and do not know regarding the pore’s molecular composition.
Literature
1.
Alcalá S, Klee M, Fernández J, Fleischer A, Pimentel-Muiños FX (2008) A high-throughput screening for mammalian cell death effectors identifies the mitochondrial phosphate carrier as a regulator of cytochrome c release. Oncogene 27:44–54PubMedCrossRef
2.
Akao M, O’Rourke B, Kusuoka H, Teshima Y, Jones SP, Marbán E (2003) Differential actions of cardioprotective agents on the mitochondrial death pathway. Circ Res 92:195–202PubMedCrossRef
3.
Antonsson B, Montessuit S, Lauper S, Eskes R, Martinou JC (2000) Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J 345:271–278PubMedCrossRef
4.
Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M (2005) Postconditioning inhibits mitochondrial permeability transition. Circulation 111:194–197PubMedCrossRef
5.
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 434:658–662PubMedCrossRef
6.
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 9:550–555PubMedCrossRef
7.
Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P (2005) Properties of the permeability transition pore in mitochondria devoid of cyclophilin D. J Biol Chem 280:18558–18561PubMedCrossRef
8.
Bauer MK, Schubert A, Rocks O, Grimm S (1999) Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis. J Cell Biol 147:1493–1502PubMedCrossRef
9.
Belzacq AS, Vieira HL, Kroemer G, Brenner C (2002) The adenine nucleotide translocator in apoptosis. Biochimie 84:167–176PubMedCrossRef
10.
Belzacq AS, Vieira HL, Verrier F, Vandecasteele G, Cohen I, Prevost MC, Larquet E, Pariselli F, Petit PX, Kahn A, Rizzuto R, Brenner C, Kroemer G (2003) Bcl-2 and Bax modulate adenine nucleotide translocase activity. Cancer Res 63:541–546PubMed
11.
12.
Brower JV, Rodic N, Seki T, Jorgensen M, Fliess N, Yachnis AT, McCarrey JR, Oh SP, Terada N (2007) Evolutionarily conserved mammalian adenine nucleotide translocase 4 is essential for spermatogenesis. J Biol Chem 282:29658–29666PubMedCrossRef
13.
Cesura AM, Pinard E, Schubenel R, Goetschy V, Friedlein A, Langen H, Polcic P, Forte MA, Bernardi P, Kemp JA (2003) The voltage-dependent anion channel is the target for a new class of inhibitors of the mitochondrial permeability transition pore. J Biol Chem 278:49812–49818PubMedCrossRef
14.
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 280:H2313–H2320
15.
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 277:34793–34799PubMedCrossRef
16.
Crompton M, Virji S, Ward JM (1998) Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. Eur J Biochem 258:729–735PubMedCrossRef
17.
Crow MT, Mani K, Nam YJ, Kitsis RN (2004) The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res 95:957–970PubMedCrossRef
18.
de Macedo DV, Nepomuceno ME, Pereira-da-Silva L (1993) Involvement of the ADP/ATP carrier in permeabilization processes of the inner mitochondrial membrane. Eur J Biochem 215:595–600PubMedCrossRef
19.
De Marchi U, Campello S, Szabò I, Tombola F, Martinou JC, Zoratti M (2004) Bax does not directly participate in the Ca2+-induced permeability transition of isolated mitochondria. J Biol Chem 279:37415–37422PubMedCrossRef
20.
Di Lisa F, Canton M, Menabò R, Kaludercic N, Bernardi P (2007) Mitochondria and cardioprotection. Heart Fail Rev 12:249–260PubMedCrossRef
21.
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 276:2571–2575PubMedCrossRef
22.
Diwan A, Krenz M, Syed FM, Wansapura J, Ren X, Koesters AG, Li H, Kirshenbaum LA, Hahn HS, Robbins J, Jones WK, Dorn GW (2007) Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. J Clin Invest 117:2825–2833PubMedCrossRef
23.
Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR (1999) Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem 274:2225–2233PubMedCrossRef
24.
Fiore C, Trézéguet V, Le Saux A, Roux P, Schwimmer C, Dianoux AC, Noel F, Lauquin GJ, Brandolin G, Vignais PV (1998) The mitochondrial ADP/ATP carrier: structural, physiological and pathological aspects. Biochimie 80:137–150PubMedCrossRef
25.
Griffiths EJ, Halestrap AP (1995) Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J 307:93–98PubMed
26.
Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13:1899–1911PubMedCrossRef
27.
Gustafsson AB, Gottlieb RA (2008) Heart mitochondria: gates of life and death. Cardiovasc Res 77:334–343PubMedCrossRef
28.
Halestrap AP, Clarke SJ, Javadov SA (2004) Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc Res 61:372–385PubMedCrossRef
29.
Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, Gottlieb RA, Gustafsson AB (2007) Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 14:146–157PubMedCrossRef
30.
Hausenloy DJ, Duchen MR, Yellon DM (2003) Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res 60:617–625PubMedCrossRef
31.
Haworth RA, Hunter DR (2000) Control of the mitochondrial permeability transition pore by high-affinity ADP binding at the ADP/ATP translocase in permeabilized mitochondria. J Bioenerg Biomembr 32:91–96PubMedCrossRef
32.
Hochhauser E, Kivity S, Offen D, Maulik N, Otani H, Barhum Y, Pannet H, Shneyvays V, Shainberg A, Goldshtaub V, Tobar A, Vidne BA (2003) Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice. Am J Physiol 284:H2351–H2359
33.
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 95:734–741PubMedCrossRef
34.
Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP (2003) Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol 549:513–524PubMedCrossRef
35.
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 113:1535–1549PubMed
36.
Jürgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC (1998) Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci 95:4997–5002PubMedCrossRef
37.
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 12:908–916PubMedCrossRef
38.
Kokoszka J, 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 427:461–465PubMedCrossRef
39.
Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7:1166–1173PubMedCrossRef
40.
Krauskopf A, Eriksson O, Craigen WJ, Forte MA, Bernardi P (2006) Properties of the permeability transition in VDAC1−/− mitochondria. Biochim Biophys Acta 1757:590–595PubMedCrossRef
41.
Kroemer G (2003) The mitochondrial permeability transition pore complex as a pharmacological target. An introduction. Curr Med Chem 10:1469–1472PubMedCrossRef
42.
Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial permeabilization in cell death. Physiol Rev 87:99–163PubMedCrossRef
43.
Lazou A, Iliodromitis EK, Cieslak D, Voskarides K, Mousikos S, Bofilis E, Kremastinos DT (2006) Ischemic but not mechanical preconditioning attenuates ischemia/reperfusion induced myocardial apoptosis in anaesthetized rabbits: the role of Bcl-2 family proteins and ERK1/2. Apoptosis 11:2195–2204PubMedCrossRef
44.
Leung AW, Varanyuwatana P, Halestrap AP (2008) The mitochondrial phosphate carrier interacts with cyclophilin D and may play a key role in the permeability transition. J Biol Chem 283:26312–26323PubMedCrossRef
45.
Leung AW, Halestrap AP (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777:946–952PubMedCrossRef
46.
Lim SY, Davidson SM, Hausenloy DJ, Yellon DM (2007) Preconditioning and postconditioning: the essential role of the mitochondrial permeability transition pore. Cardiovasc Res 75:530–535PubMedCrossRef
47.
Marzo I, Brenner C, Zamzami N, Jurgensmeier JM, Susin SA, Vieira HL, Prevost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G (1998) Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281:2027–2031PubMedCrossRef
48.
Maulik N, Engelman RM, Rousou JA, Flack JE 3rd, Deaton D, Das DK (1999) Ischemic preconditioning reduces apoptosis by upregulating anti-death gene Bcl-2. Circulation 100:II369–II375PubMed
49.
Mikhailov V, Mikhailova M, Degenhardt K, Venkatachalam MA, White E, Saikumar P (2003) Association of Bax and Bak homo-oligomers in mitochondria Bax requirement for Bak reorganization and cytochrome c release. J Biol Chem 278:5367–5376PubMedCrossRef
50.
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 14:442–447PubMedCrossRef
51.
Murphy E, Steenbergen C (2008) Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 88:581–609PubMedCrossRef
52.
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 434:652–658PubMedCrossRef
53.
Nakayama N, Chen X, Baines CP, Klevitsky R, Zhang H, Jaleel N, Chua BHL, Zhang X, 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 117:2431–2444PubMedCrossRef
54.
Oliveira PJ, Seica R, Coxito PM, Rolo AP, Palmeira CM, Santos MS, Moreno AJ (2003) Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats. FEBS Lett 554:511–514PubMedCrossRef
55.
Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47:143–183PubMedCrossRef
56.
Pastorino JG, Chen ST, Tafani M, Snyder JW, Farber JL (1998) The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem 273:7770–7775PubMedCrossRef
57.
Pastorino JG, Tafani M, Rothman RJ, Marcinkeviciute A, Hoek JB, Farber JL (1999) Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J Biol Chem 274:31734–31739PubMedCrossRef
58.
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 359:473–481PubMedCrossRef
59.
Polcic P, Forte M (2003) Response of yeast to the regulated expression of proteins in the Bcl-2 family. Biochem J 374:393–402PubMedCrossRef
60.
Priault M, Chaudhuri B, Clow A, Camougrand N, Manon S (1999) Investigation of bax-induced release of cytochrome c from yeast mitochondria permeability of mitochondrial membranes, role of VDAC and ATP requirement. Eur J Biochem 260:684–691PubMedCrossRef
61.
Regula KM, Kirshenbaum LA (2005) Apoptosis of ventricular myocytes: a means to an end. J Mol Cell Cardiol 38:3–13PubMedCrossRef
62.
Rostovtseva TK, Tan W, Colombini M (2005) On the role of VDAC in apoptosis: fact and fiction. J Bioenerg Biomembr 37:129–142PubMedCrossRef
63.
Schinzel A, 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 102:12005–12010PubMedCrossRef
64.
Sharpe JC, Arnoult D, Youle RJ (2004) Control of mitochondrial permeability by Bcl-2 family members. Biochim Biophys Acta 1644:107–113PubMedCrossRef
65.
Shimizu S, Shinohara Y, Tsujimoto Y (2000) Bax and Bcl-xL independently regulate apoptotic changes of yeast mitochondria that require VDAC but not adenine nucleotide translocator. Oncogene 19:4309–4318PubMedCrossRef
66.
Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487PubMedCrossRef
67.
Toth A, Jeffers JR, Nickson P, Min JY, Morgan JP, Zambetti GP, Erhardt P (2006) Targeted deletion of Puma attenuates cardiomyocyte death and improves cardiac function during ischemia-reperfusion. Am J Physiol 291:H52–H60
68.
von Ahsen O, Renken C, Perkins G, Kluck RM, Bossy-Wetzel E, Newmeyer DD (2000) Preservation of mitochondrial structure and function after Bid- or Bax-mediated cytochrome c release. J Cell Biol 150:1027–1036CrossRef
69.
Vyssokikh MY, Katz A, Rueck A, Wuensch C, Dorner A, Zorov DB, Brdiczka D (2001) Adenine nucleotide translocator isoforms 1 and 2 are differently distributed in the mitochondrial inner membrane and have distinct affinities to cyclophilin D. Biochem J 358:349–358PubMedCrossRef
70.
Walther T, Tschöpe C, Sterner-Kock A, Westermann D, Heringer-Walther S, Riad A, Nikolic A, Wang Y, Ebermann L, Siems WE, Bader M, Shakibaei M, Schultheiss HP, Dörner A (2007) Accelerated mitochondrial adenosine diphosphate/adenosine triphosphate transport improves hypertension-induced heart disease. Circulation 115:333–344PubMedCrossRef
71.
72.
Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14:2060–2071PubMed
73.
Weiss JN, Korge P, Honda HM, Ping P (2003) Role of the mitochondrial permeability transition in myocardial disease. Circ Res 93:292–301PubMedCrossRef
74.
Woodfield K, Ruck A, Brdiczka D, Halestrap AP (1998) Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem J 336:287–290PubMed
75.
Zamora M, Granell M, Mampel T, Vinas O (2004) Adenine nucleotide translocase 3 (ANT3) overexpression induces apoptosis in cultured cells. FEBS Lett 563:155–160PubMedCrossRef
76.
Zhao ZQ, Nakamura M, Wang NP, Wilcox JN, Shearer S, Ronson RS, Guyton RA, Vinten-Johansen J (2000) Reperfusion induces myocardial apoptotic cell death. Cardiovasc Res 45:651–660PubMedCrossRef
77.
Zheng Y, Shi Y, Tian C, Jiang C, Jin H, Chen J, Almasan A, Tang H, Chen Q (2004) Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide. Oncogene 23:1239–1247PubMedCrossRef
Metadata
Title
The mitochondrial permeability transition pore and ischemia-reperfusion injury
Author
Christopher P. Baines
Publication date
01-03-2009
Publisher
D. Steinkopff-Verlag
Published in
Basic Research in Cardiology / Issue 2/2009
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI
https://doi.org/10.1007/s00395-009-0004-8

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