Abstract
The permeability transition pore (PT-pore) is a multi-component protein aggregate in mitochondria that comprises factors in the inner as well as in the outer mitochondrial membrane. This complex has two functions: firstly, it regulates the integration of oxidative phosphorylation into the cellular energy household and secondly, it induces cell death when converted into an unspecific channel. The latter causes a collapse of the mitochondrial membrane potential and activates a chain of events that culminate in the demise of the cell. It has been controversial for some time whether the PT-pore is causative for or only amplifies a signal of cell death but novel results confirm a central role of this protein complex for cell death induction. While a considerable body of data exist on its subunit composition, recent genetic knock-out experiments suggest that the identity of the core factors of the PT-pore is still unresolved. Moreover, accumulating evidence point to a much more complex composition of this protein complex than anticipated. Here, we review the current knowledge of its subunit composition, the evidence of a role in cell death, and we propose a model for the activation of the PT-pore for cell death.
Article PDF
Similar content being viewed by others
References
Bernardi P, Krauskopf A, Basso E et al (2006) The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J 273:2077–2099
Kroemer G (1997) Mitochondrial implication in apoptosis. Towards an endosymbiont hypothesis of apoptosis evolution. Cell Death Differ 4:443–456
Kroemer G, Zamzami N, Susin SA (1997) Mitochondrial control of apoptosis. Immunol Today 18:44–51
Boise LH, Thompson CB (1997) Bcl-x(L) can inhibit apoptosis in cells that have undergone Fas-induced protease activation. Proc Natl Acad Sci USA 94:3759–3764
Miossec C, Dutilleul V, Fassy F, Diu-Hercend A (1997) Evidence for CPP32 activation in the absence of apoptosis during T lymphocyte stimulation. J Biol Chem 272:13459–13462
Lesage S, Steff AM, Philippoussis F et al (1997) CD4+ CD8+ thymocytes are preferentially induced to die following CD45 cross-linking, through a novel apoptotic pathway. J Immunol 159:4762–4771
Lavoie JN, Nguyen M, Marcellus RC, Branton PE, Shore GC (1998) E4orf4, a novel adenovirus death factor that induces p53-independent apoptosis by a pathway that is not inhibited by zVAD-fmk. J Cell Biol 140:637–645
He L, Lemasters JJ (2002) Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function? FEBS Lett 512:1–7
Bernardi P, Scorrano L, Colonna R, Petronilli V, Di Lisa F (1999) Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur J Biochem 264:687–701
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 273:7770–7775
Narita M, Shimizu S, Ito T et al (1998) Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc Natl Acad Sci USA 95:14681–14686
Marzo I, Brenner C, Zamzami N et al (1998) Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281:2027–2031
Zamzami N, Brenner C, Marzo I, Susin SA, Kroemer G (1998) Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene 16:2265–2282
Halestrap AP, Brenner C (2003) The adenine nucleotide translocase: a central component of the mitochondrial permeability transition pore and key player in cell death. Curr Med Chem 10:1507–1525
Brustovetsky N, Klingenberg M (1996) Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+. Biochemistry 35:8483–8488
Martinou I, Desagher S, Eskes R et al (1999) The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible event. J Cell Biol 144:883–889
Jurgensmeier JM, Xie Z, Deveraux Q et al (1998) Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA 95:4997–5002
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 274:2225–2233
Kluck RM, Esposti MD, Perkins G et al (1999) The pro-apoptotic proteins, Bid and Bax, cause a limited permeabilization of the mitochondrial outer membrane that is enhanced by cytosol. J Cell Biol 147:809–822
Eskes R, Antonsson B, Osen-Sand A et al (1998) Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ions. J Cell Biol 143:217–224
Scorrano L, Ashiya M, Buttle K et al (2002) A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Developmental Cell 2:55–67
Desagher S, Martinou JC (2000) Mitochondria as the central control point of apoptosis. Trends Cell Biol 10:369–377
Yang J, Liu X, Bhalla K et al (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275:1129–1132
Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:1132–1136
Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR (2000) The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol 2:156–162
Bossy-Wetzel E, Newmeyer DD, Green DR (1998) Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 17:37–49
Deshmukh M, Kuida K, Johnson EM Jr (2000) Caspase inhibition extends the commitment to neuronal death beyond cytochrome c release to the point of mitochondrial depolarization. J Cell Biol 150:131–143
Marzo I, Brenner C, Zamzami N et al (1998) The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins. J Exp Med 187:1261–1271
Susin SA, Zamzami N, Castedo M et al (1997) The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. J Exp Med 186:25–37
Pastorino JG, Tafani M, Rothman RJ et al (1999) Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J Biol Chem 274:31734–31739
Jouaville LS, Ichas F, Mazat JP (1998) Modulation of cell calcium signals by mitochondria. Mol Cell Biochem 184:371–376
Ichas F, Jouaville LS, Mazat JP (1997) Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89:1145–1153
Scorrano L, Ashiya M, Buttle K et al (2002) A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2:55–67
Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185:1481–1486
Crompton M, Costi A (1988) Kinetic evidence for a heart mitochondrial pore activated by Ca2+, inorganic phosphate and oxidative stress. A potential mechanism for mitochondrial dysfunction during cellular Ca2+ overload. Eur J Biochem 178:489–501
Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341:233–249
Crompton M, Costi A (1990) A heart mitochondrial Ca2(+)-dependent pore of possible relevance to re-perfusion-induced injury. Evidence that ADP facilitates pore interconversion between the closed and open states. Biochem J 266:33–39
Jacobson J, Duchen MR (2002) Mitochondrial oxidative stress and cell death in astrocytes–requirement for stored Ca2+ and sustained opening of the permeability transition pore. J Cell Sci 115:1175–1188
Halestrap AP (1999) The mitochondrial permeability transition: its molecular mechanism and role in reperfusion injury. Biochem Soc Symp 66:181–203
Roos N, Benz R, Brdiczka D (1982) Identification and characterization of the pore-forming protein in the outer membrane of rat liver mitochondria. Biochim Biophys Acta 686:204–214
Benz R (1994) Permeation of hydrophilic solutes through mitochondrial outer membranes: Review on mitochondrial porins. Biochim Biophys Acta 1197:167–196
Tanveer A, Virji S, Andreeva L et al (1996) Involvement of cyclophilin D in the activation of a mitochondrial pore by Ca2+ and oxidant stress. Eur J Biochem 238:166–172
Debatin KM, Poncet D, Kroemer G (2002) Chemotherapy: targeting the mitochondrial cell death pathway. Oncogene 21:8786–8803
Beutner G, Ruck A, Riede B, Brdiczka D (1998) Complexes between porin, hexokinase, mitochondrial creatine kinase and adenylate translocator display properties of the permeability transition pore. Implication for regulation of permeability transition by the kinases. Biochim Biophys Acta 1368:7–18
De Pinto V, Prezioso G, Thinnes F, Link TA, Palmieri F (1991) Peptide-specific antibodies and proteases as probes of the transmembrane topology of the bovine heart mitochondrial porin. Biochemistry 30:10191–10200
Colombini M (2004) VDAC: the channel at the interface between mitochondria and the cytosol. Mol Cell Biochem 256–257:107–115
Reymann S, Thinnes F et al (1995) Further evidence for multitopological localization of mammalian porin (VDAC) in the plasmalemma forming part of a chloride channel complex affected in cystic fibrosis and encephalomyopathy. Biochem Mol Med 54:75–87
DePinto V, Benz R, Palmieri F (1989) Interaction of non-classical detergents with the mitochondrial porin. A new purification procedure and characterization of the pore-forming unit. Eur J Biochem 183:179–187
Thomas L, Blachly-Dyson E, Colombini M, Forte M (1993) Mapping of residues forming the voltage sensor of the voltage-dependent anion-selective channel. Proc Natl Acad Sci USA 90:5446–5449
Song J, Midson C, Blachly-Dyson E, Forte M, Colombini M (1998) The topology of VDAC as probed by biotin modification. J Biol Chem 273:24406–24413
Rostovtseva TK, Liu TT, Colombini M, Parsegian VA, Bezrukov SM (2000) Positive cooperativity without domains or subunits in a monomeric membrane channel. Proc Natl Acad Sci USA 97:7819–7822
Krause J, Hay R, Kowollik C, Brdiczka D (1986) Cross-linking analysis of yeast mitochondrial outer membrane. Biochim Biophys Acta 860:690–698
Linden M, Gellerfors P (1983) Hydrodynamic properties of porin isolated from outer membranes of rat liver mitochondria. Biochim Biophys Acta 736:125–129
Shoshan-Barmatz V, Zalk R, Gincel D, Vardi N (2004) Subcellular localization of VDAC in mitochondria and ER in the cerebellum. Biochim Biophys Acta 1657:105–114
Zalk R, Israelson A, Garty ES, Azoulay-Zohar H, Shoshan-Barmatz V (2005) Oligomeric states of the voltage-dependent anion channel and cytochrome c release from mitochondria. Biochem J 386:73–83
Martin W, Hoffmeister M, Rotte C, Henze K (2001) An overview of endosymbiotic models for the origins of eukaryotes, their ATP-producing organelles (mitochondria and hydrogenosomes), and their heterotrophic lifestyle. Biol Chem 382:1521–1539
Gumaa KA, McLean P, Greenbaum AL (1971) Compartmentation in relation to metabolic control in liver. Essays Biochem 7:39–86
Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J 281:21–40
Saks V, Dzeja P, Schlattner U et al (2006) Cardiac system bioenergetics: metabolic basis of the Frank-Starling law. J Physiol 571:253–273
Bernardi P, Azzone GF (1981) Cytochrome c as an electron shuttle between the outer and inner mitochondrial membranes. J Biol Chem 256:7187–7192
Marzulli D, La Piana G, Franseve E, Lofrumento NE (1999) Modulation of cytochrome c- mediated extramitochondrial NADH oxidation by contact site structure. Biochem Biophys Res Commun 259:325–330
Brdiczka D, Zorov DB, Sheu SS (2006) Mitochondrial contact sites: their role in energy metabolism and apoptosis. Biochim Biophys Acta 1762:148–163
Schein SJ, Colombini M, Finkelstein A (1976) Reconstitution in planar lipid bilayers of a voltage-dependent anion-selective channel obtained from paramecium mitochondria. J Membr Biol 30:99–120
Ruck A, Dolder M, Wallimann T, Brdiczka D (1998) Reconstituted adenine nucleotide translocase forms a channel for small molecules comparable to the mitochondrial permeability transition pore. FEBS Lett 426:97–101
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 258:729–735
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 336:287–290
Schlatter D, Thoma R, Kung E et al (2005) Crystal engineering yields crystals of cyclophilin D diffracting to 1.7 A resolution. Acta Crystallogr D Biol Crystallogr 61:513–519. Epub 2005 April 20
Vyssokikh MY, Katz A, Rück A et al (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 358:349–358
Fiek C, Benz R, Roos N, Brdiczka D (1982) Evidence for identity between the hexokinase-binding protein and the mitochondrial porin in the outer membrane of rat liver mitochondria. Biochim Biophys Acta 688:429–440
Lindén M, Gellerfors P, Nelson BD (1982) Pore protein and the hexokinase-binding protein from the outer membrane of rat liver mitochondria are identical. FEBS-Letters 141:189–192
Brdiczka D, Kaldis P, Wallimann T (1994) In vitro complex formation between octamer of creatine kinase and porin. J Biol Chem 269:27640–27644
Wilson JE (1978) Ambiquitous enzymes: variation in intracellular distribution as a regulatory mechanism. Trends Biochem Sci 3:124–125
Wicker U, Bücheler K, Gellerich FN et al (1993) Effect of macromolecules on the structure of the mitochondrial inter-membrane space and the regulation of hexokinase. Biochim Biophys Acta 1142:228–239
Knoll G, Brdiczka D (1983) Changes in freeze-fracture mitochondrial membranes correlated to their energetic state. Biochim Biophys Acta 733:102–110
Laterveer FD, Gellerich FN, Nicolay K (1995) Macromolecules increase the channeling of ADP from externally associated hexokinase to the matrix of mitochondria. Eur J Biochem 232:569–577
Xie G, Wilson JE (1990) Tetrameric structure of mitochondrially bound rat brain hexokinase: a crossliking study. Arch Biochem Biophys 276:285–293
Hashimoto M, Wilson JE (2000) Membrane potential-dependent conformational changes in mitochondrially bound hexokinase in brain. Arch Biochem Biophys 884:163–173
Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH (2002) Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim Biophys Acta 1555:14–20
Penso J, Beitner R (1998) Clotrimazole and bifonazole detach hexokinase from mitochondria of melanoma cells. Eur J Pharmacol 342:113–117
Ibsen HK (1961) The Crabtree effect: a review. Cancer Res 21:829–841
Denis-Pouxviel C, Riesinger I, Bühler C, Brdiczka D, Murat J-C (1987) Regulation of mitochondrial hexokinase in cultured HT 29 human cancer cells. Biochim Biophys Acta 902:335–348
Bücheler K, Adams V, Brdiczka D (1991) Localization of the ATP/ADP translocator in the inner membrane and regulation of contact sites between mitochondrial envelope membranes by ADP. A study on freeze fractured isolated liver mitochondria. Biochim Biophys Acta 1061:215–225
Ohlendieck K, Riesinger I, Adams V, Krause J, Brdiczka D (1986) Enrichment and biochemical characterization of boundary membrane contact sites from rat-liver mitochondria. Biochim Biophys Acta 860:672–689
Adams V, Bosch W, Schlegel J, Wallimann T, Brdiczka D (1989) Further characterization of contact sites from mitochondria of different tissues: toplogy of peripheral kinases. Biochim Biophys Acta 981:213–225
Vyssokikh MY, Zorova L, Zorov D et al (2004) The intra-mitochondrial cytochrome c distribution varies correlated to the formation of a complex between VDAC and the adenine nucleotide translocase: this affects Bax-dependent cytochrome c release. Biochim Biophys Acta 1644:27–36
Beutner G, Rück A, Riede B, Welte W, Brdiczka D (1996) Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore. FEBS Lett 396:189–195
Beutner G, Ruck A, Riede B, Brdiczka D (1997) Complexes between hexokinase, mitochondrial porin and adenylate translocator in brain: regulation of hexokinase, oxidative phosphorylation and permeability transition pore. Biochem Soc Trans 25:151–157
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 258:729–735
Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86:147–157
Martinou JC, Desagher S, Antonsson B (2000) Cytochrome c release from mitochondria: all or nothing. Nat Cell Biol 2:E41–E43
Doran E, Halestrap AP (2000) Cytochrome c release from isolated rat liver mitochondria can occur independently of outer-membrane rupture: possible role of contact sites. Biochem J :343–350
Freitag H, Neupert W, Benz R (1982) Purification and characterization of a pore protein of the outer mitochondrial membrane from Neurospora crassa. Eur J Biochem 162:629–636
Popp B, Schmid A, Benz R (1995) Role of sterols in the functional reconstitution of water-soluble mitochondrial porins from different organisms. Biochemistry 34:3352–3361
Daum G (1985) Lipids of mitochondria. Biochim Biophys Acta 822:1–42
Ardail D, Privat J-P, Egret-Charlier M et al (1990) Mitochondrial contact sites, lipid composition and dynamics. J Biol Chem 265:18797–18802
Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387:569–572
Vyssokikh M, Brdiczka D (2004) Function of the outer mitochondrial membrane pore (Voltage-dependent Anion Channel) in intracellular signaling. In: Benz R (ed) Bacterial and eukaryotic porins structure, function, mechanism, Wiley-VCH, Weinheim Germany, pp 339–358
Dimitroulakos J, Nohynek D, Backway KL et al (1999) Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: a potential therapeutic approach. Blood 93:1308–1318
Beyer K, Klingenberg M (1985) ADP/ATP carrier protein from beef heart mitochondria has high amounts of tightly bound cardiolipin, as revealed by 31P nuclear magnetic resonance. Biochemistry 24:3821–3826
Van Venetie R, Verkleij AJ (1982) Possible role of non-bilayer lipids in the structure of mitochondria. A freeze-fracture electron microscopy study. Biochim Biophys Acta 692:397–405
Newmeyer DD, Ferguson-Miller S (2003) Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112:481–490
Iverson SL, Orrenius S (2004) The cardiolipin-cytochrome c interaction and the mitochondrial regulation of apoptosis. Arch Biochem Biophys 423:37–46
De Giorgi F, Lartigue L, Bauer MKA et al. The permeability transition pore signals apoptosis by directing Bax translocation and multimerization. FASEB J 16:607–609
Lutter M, Fang M, Luo X et al (2000) Cardiolipin provides specificity for targeting of tBid to mitochondria. Nat Cell Biol 2:754–761
Kim TH, Zhao Y, Ding WX et al (2004) Bid-Cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome c release. Mol Biol Cell 15:3061–3072
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 336:287–290
Verrier F, Deniaud A, Lebras M et al (2004) Dynamic evolution of the adenine nucleotide translocase interactome during chemotherapy-induced apoptosis. Oncogene 23:8049–8064
Kokoszka JE, Waymire KG, Levy SE et al (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465
Kim TH, Zhao Y, Barber MJ, Kuharsky DK, Yin XM (2000) Bid-induced cytochrome c release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax. J Biol Chem 275:39474–39481
Soriano ME, Nicolosi L, Bernardi P (2004) Desensitization of the permeability transition pore by cyclosporin a prevents activation of the mitochondrial apoptotic pathway and liver damage by tumor necrosis factor-alpha. J Biol Chem 279:36803–36808. Epub 2004 Jun 16
Rodic N, Oka M, Hamazaki T et al (2005) DNA methylation is required for silencing of ant4, an adenine nucleotide translocase selectively expressed in mouse embryonic stem cells and germ cells. Stem Cells 23:1314–1323. Epub 2005 July 28
Halestrap AP (2004) Mitochondrial permeability: dual role for the ADP/ATP translocator? Nature 430:1 p following 983
Baines CP, Kaiser RA, Purcell NH et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662
Nakagawa T, Shimizu S, Watanabe T et al (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434:652–658
Basso E, Fante L, Fowlkes J et al (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 280:18558–18561. Epub 2005 March 25
Schinzel AC, Takeuchi O, Huang Z et al (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. Epub 2005 Aug 15
Forte M, Bernardi P (2005) Genetic dissection of the permeability transition pore. J Bioenerg Biomembr 37:121–128
Halestrap AP, Davidson AM (1990) Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem J 268:153–160
McGuinness O, Yafei N, Costi A, Crompton M (1990) The presence of two classes of high-affinity cyclosporin A binding sites in mitochondria. Evidence that the minor component is involved in the opening of an inner-membrane Ca(2+)-dependent pore. Eur J Biochem 194:671–679
Schubert A, Grimm S, Cyclophilin D (2004) A Component of the Permeability Transition (PT)-Pore, Is an Apoptosis Repressor. Cancer Res 64:85–93
Bauer MKA, 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 147:1493–1502
Lin DT, Lechleiter JD (2002) Mitochondrial targeted cyclophilin d protects cells from cell death by peptidyl prolyl isomerization. J Biol Chem 277:31134–31141
Li Y, Johnson N, Capano M, Edwards M, Crompton M (2004) Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis. Biochem J 383:101–109
Esposito C, Fornoni A, Cornacchia F et al (2000) Cyclosporine induces different responses in human epithelial, endothelial and fibroblast cell cultures. Kidney Int 58:123–130
Gottschalk AR, Boise LH, Thompson CB, Quintans J (1994) Identification of immunosuppressant-induced apoptosis in a murine B-cell line and its prevention by Bcl-x but not bcl-2. Proc Natl Acad Sci USA 91:7350–7354
Damoiseaux JG, Defresne MP, Reutelingsperger CP, Van Breda Vriesman PJ (2002) Cyclosporin-A differentially affects apoptosis during in vivo rat thymocyte maturation. Scand J Immunol 56:353–360
Grub S, Persohn E, Trommer WE, Wolf A (2000) Mechanisms of cyclosporine A-induced apoptosis in rat hepatocyte primary cultures. Toxicol Appl Pharmacol 163:209–220
Serkova NJ, Christians U, Benet LZ (2004) Biochemical mechanisms of cyclosporine neurotoxicity. Mol Interv 4:97–107
Waldmeier PC, Feldtrauer JJ, Qian T, Lemasters JJ (2002) Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol Pharmacol 62:22–29
Crompton M (2003) On the involvement of mitochondrial intermembrane junctional complexes in apoptosis. Curr Med Chem 10:1473–1484
Pastorino JG, Shulga N, Hoek JB (2002) Mitochondrial binding of hexokinase II inhibits bax-induced cytochrome c release and apoptosis. J. Biol. Chem. 277:7610–7618
Capano M, Crompton M (2002) Biphasic translocation of BAX to mitochondria. Biochem J 367:169–178
Gottlob K, Majewski N, Kennedy S et al (2001) Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 15:1406–1418
Majewski N, Nogueira V, Bhaskar P et al (2004) Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 16:819–830
Vyssokikh MY, Zorova L, Zorov D et al (2002) Bax releases cytochrome c preferentially from a complex between porin and adenine nucleotide translocator. Hexokinase activity suppresses this effect. Mol Biol Rep 29:93–96
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Grimm, S., Brdiczka, D. The permeability transition pore in cell death. Apoptosis 12, 841–855 (2007). https://doi.org/10.1007/s10495-007-0747-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10495-007-0747-3