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The mitochondrial membrane potential (Δψm) in apoptosis; an update

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Abstract

Mitochondrial dysfunction has been shown to participate in the induction of apoptosis and has even been suggested to be central to the apoptotic pathway. Indeed, opening of the mitochondrial permeability transition pore has been demonstrated to induce depolarization of the transmembrane potential (Δψm), release of apoptogenic factors and loss of oxidative phosphorylation. In some apoptotic systems, loss of Δψm may be an early event in the apoptotic process. However, there are emerging data suggesting that, depending on the model of apoptosis, the loss of Δψm may not be an early requirement for apoptosis, but on the contrary may be a consequence of the apoptotic-signaling pathway. Furthermore, to add to these conflicting data, loss of Δψm has been demonstrated to not be required for cytochrome c release, whereas release of apoptosis inducing factor AIF is dependent upon disruption of Δψm early in the apoptotic pathway. Together, the existing literature suggests that depending on the cell system under investigation and the apoptotic stimuli used, dissipation of Δψm may or may not be an early event in the apoptotic pathway. Discrepancies in this area of apoptosis research may be attributed to the fluorochromes used to detect Δψm. Differential degrees of sensitivity of these fluorochromes exist, and there are also important factors that contribute to their ability to accurately discriminate changes in Δψm.

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References

  1. Kerr JF, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239–257.

    Google Scholar 

  2. Arends MJ, Wyllie AH. Apoptosis: Mechanisms and roles in pathology. Int Rev Exp Pathol 1991; 32: 223–254.

    Google Scholar 

  3. Schwartzman RA, Cidlowski JA. Apoptosis: The biochemistry and molecular biology of programmed cell death. Endocr Rev 1993; 14: 133–151.

    Google Scholar 

  4. Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature 2000; 407: 784–788.

    Google Scholar 

  5. Falasca L, Bergamini A, Serafino A, Balabaud C, Dini L. Human Kupffer cell recognition and phagocytosis of apoptotic peripheral blood lymphocytes. Exp Cell Res 1996; 224: 152–162.

    Google Scholar 

  6. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 1992; 148: 2207–2216.

    Google Scholar 

  7. Mühlenbeck F, Haas E, Schwenzer R, et al. TRAIL/Apo2L activates c-Jun NH2-terminal kinase (JNK) via caspasedependent and caspase-independent pathways. J Biol Chem 1998; 273: 33091–33098.

    Google Scholar 

  8. Sharma K, Wang RX, Zhang LY, et al. Death the Fas way: Regulation and pathophysiology of CD95 and its ligand. Pharmacol Ther 2000; 88: 333–347.

    Google Scholar 

  9. Silke J, Vaux DL. Cell death: Shadow baxing. Curr Biol 1998; 8: 528–531.

    Google Scholar 

  10. Korsmeyer SJ, Wie MC, Saito M, Weiler S, Oh KJ, Schlesinger PH. Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 2000; 7: 1166–1173.

    Google Scholar 

  11. Yin X-M. Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways. Cell Res 2000; 10: 161–167.

    Google Scholar 

  12. Duchen MR. Mitochondria and calcium: From cell signaling to cell death. J Physiol 2000; 529: 57–68.

    Google Scholar 

  13. McConkey DJ, Orrenius S. The role of calcium in the regulation of apoptosis. J Leukocyte Biol 1996; 59: 775–783.

    Google Scholar 

  14. Creagh EM, Martin SJ. Caspases: Cellular demolition experts. Biochem Soc Trans 2001; 29: 696–702.

    Google Scholar 

  15. Zou H, Li Y, Liu X, Wang X. An APAF-1·cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999; 274: 11549–11556.

    Google Scholar 

  16. Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW. Three-dimensional structure of the apoptosome: Implications for assembly, procaspase-9 binding, and activation. Mol Cell 2002; 9: 423–432.

    Google Scholar 

  17. Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309–1312.

    Google Scholar 

  18. Desagher S, Martinou J-C. Mitochondria as the central control point of apoptosis. Trends Cell Biol 2000; 10: 369–377.

    Google Scholar 

  19. Leist M, Nicotera P. The shape of cell death. Biochem Biophys Res Commun 1997; 236: 1–9.

    Google Scholar 

  20. Vayssière J-L, Petit PX, Risler Y, Mignotte B. Commitment to apoptosis is associated with changes in mitochondrial biogenesis and activity in cell lines conditionally immortalized with simian virus 40. Proc Natl Acad Sci USA 1994; 91: 11752–11756.

    Google Scholar 

  21. Zoratti M, Szabó I. The mitochondrial permeability transition. Biochim Biophys Acta 1995; 1241: 139–176.

    Google Scholar 

  22. Kroemer G, Reed JC. Mitochondrial control of cell death. Nat Med 2000; 6: 513–519.

    Google Scholar 

  23. Finkel E. The Mitochondrion: Is it central to apoptosis? Science 2001; 292: 624–626.

    Google Scholar 

  24. Smaili SS, Hsu YT, Youle RJ, Russell JT. Mitochondria in Ca2+ signaling and apoptosis. J Bioenerg Biomembr 2000; 32: 35–46.

    Google Scholar 

  25. Szabó I, De Pinto V, Zoratti M. The mitochondrial permeability transition pore may comprise VDAC molecules. II. The electrophysiological properties of VDAC are compatible with those of the mitochondrial megachannel. FEBS Lett 1993; 330: 206–210.

    Google Scholar 

  26. Szabó I, Zoratti M. The mitochondrial permeability transition pore may comprise VDAC molecules. I. Binary structure and voltage dependence of the pore. FEBS Lett 1993; 330: 201–205.

    Google Scholar 

  27. Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J 1999; 341: 233–249.

    Google Scholar 

  28. Halestrap AP, McStay GP, Clarke SJ. The permeability transition pore complex: Another view. Biochimie 2002; 84: 153–166.

    Google Scholar 

  29. Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nature Med 1997; 3: 614–620.

    Google Scholar 

  30. Bossy-Wetzel E, Newmeyer DD, Green DR. Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 1998; 17: 37–49.

    Google Scholar 

  31. Petronilli V, Cola C, Massari S, Colonna R, Bernardi P. Physiological effectors modify voltage sensing by the cyclosporin A-sensitive permeability transition pore of mitochondria. J Biol Chem 1993; 268: 21939–21945.

    Google Scholar 

  32. Bernardi P, Vassanelli S, Veronese P, Colonna R, Szabó I, Zoratti M. Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations. J Biol Chem 1992; 267: 2934–2939.

    Google Scholar 

  33. Ichas F, Mazat J-P. 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: 33–50.

    Google Scholar 

  34. Nieminen AL, Saylor AK, Tesfai SA, Herman B, Lemasters JJ. Contribution of the mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t-butylhydroperoxide. Biochem J 1995; 307: 99–106.

    Google Scholar 

  35. Lemasters JJ, Nieminen A-L, Qian T, Trost LC, Herman B. The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury. Mol Cell Biochem 1997; 174: 159–165.

    Google Scholar 

  36. Gottlieb RA. Mitochondria and apoptosis. Biol Signals Recept 2001; 10: 147–161.

    Google Scholar 

  37. Zamzami N, Marchetti P, Castedo M, et al. Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J Exp Med 1995; 181: 1661–1672.

    Google Scholar 

  38. Więckowski MR, Wojtczak L. Fatty acid-induced uncoupling of oxidative phosphorylation is partly due to opening of the mitochondrial permeability transition pore. FEBS Lett 1998; 423: 339–342.

    Google Scholar 

  39. Moret V, Lorini M, Fotia A, Siliprandi N. Effect of atractyloside on the binding of adenine nucleotides to the mitochondrial “structural protein”. Biochim Biophys Acta 1966; 124: 433–435.

    Google Scholar 

  40. Winkler HH, Lehninger AL. The atractyloside-sensitive nucleotide binding site in a membrane preparation from rat liver mitochondria. J Biol Chem 1968; 243: 3000–3008.

    Google Scholar 

  41. Henderson PJ, Lardy HA. Bongkrekic acid. An inhibitor of the adenine nucleotide translocase of mitochondria. J Biol Chem 1970; 245: 1319–1326.

    Google Scholar 

  42. Jung K, Pergande M. Influence of cyclosporin A on the respiration of isolated rat kidney mitochondria. FEBS Lett 1985; 183: 167–169.

    Google Scholar 

  43. Crompton M, Ellinger H, Costi A. Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem J 1988; 255: 357–360.

    Google Scholar 

  44. Broekemeier KM, Dempsey ME, Pfeiffer DR. Cyclosporin A is a potent inhibitor of the inner membrane permeability transition in liver mitochondria. J Biol Chem 1989; 264: 7826–7830.

    Google Scholar 

  45. Halestrap AP, Davidson AM. 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 1990; 268: 153–160.

    Google Scholar 

  46. Haworth RA, Hunter DR. The Ca2+-induced membrane transition in mitochondria. Nature of the Ca2+ trigger site. Arch Biochem Biophys 1979; 195: 460–467.

    Google Scholar 

  47. Griffiths EJ, Halestrap AP. Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. Implications for the immunosuppressive and toxic effects of cyclosporin. Biochem J 1991; 274: 611–614.

    Google Scholar 

  48. Crompton M, McGuinness O, Nazareth W. The involvement of cyclosporin A binding proteins in regulating and uncoupling mitochondrial energy transduction. Biochim Biophys Acta 1992; 1101: 214–217.

    Google Scholar 

  49. Woodfield K, Rück A, Brdiczka D, Halestrap AP. Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem J 1998; 336: 287–290.

    Google Scholar 

  50. Azzi A, Azzone GF. Swelling and shrinkage phenomena in liver mitochondria. Irreversible swelling induced by inorganic phosphate and Ca2+. Biochim Biophys Acta 1966; 113: 438–444.

    Google Scholar 

  51. Novgorodov SA, Gudz TI, Jung DW, Brierley GP. The nonspecific inner membrane pore of liver mitochondria: Modulation of cyclosporin sensitivity by ADP at carboxyatractyloside-sensitive and insensitive sites. Biochem Biophys Res Commun 1991; 180: 33–38.

    Google Scholar 

  52. Beatrice MC, Stiers DL, Pfeiffer DR. Increased permeability of mitochondria during Ca2+ release induced by t-butyl hydroperoxide or oxalacetate. The effect of ruthenium red. J Biol Chem 1982; 257: 7161–7171.

    Google Scholar 

  53. Takei N, Endo Y. Ca2+ ionophore-induced apoptosis on cultured embryonic rat cortical neurons. Brain Res 1994; 652: 65–70.

    Google Scholar 

  54. Hatanaka Y, Suzuki K, Kawasaki Y, Endo Y, Taniguchi N, Takei N. A role of peroxides in Ca2+ ionophore-induced apoptosis in cultured rat cortical neurons. Biochem Biophys Res Commun 1996; 227: 513–518.

    Google Scholar 

  55. Klaidman LK, Mukherjee SK, Hutchin TP, Adams JD. Nicotinamide as a precursor for NAD+ prevents apoptosis in the mouse brain induced by tertiary-butylhydroperoxide. Neurosci Lett 1996; 206: 5–8.

    Google Scholar 

  56. Brdiczka D, Beutner G, Rück A, Dolder M, Wallimann T. The molecular structure of mitochondrial contact sites. Their role in regulation of energy metabolism and permeability transition. Biofactors 1998; 8: 235–242.

    Google Scholar 

  57. Beutner G, Rück A, Riede B, Brdiczka D. 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 1998; 1368: 7–18.

    Google Scholar 

  58. Nicolli A, Petronilli V, Bernardi P. Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore by matrix pH. Evidence that the pore open-closed probability is regulated by reversible histidine protonation. Biochemistry 1993; 32: 4461–4465.

    Google Scholar 

  59. Costantini P, Chernyak BV, Petronilli V, Bernardi P. Modulation of the mitochondrial permeability transition pore by pyridine nucleotides and dithiol oxidation at two separate sites. J Biol Chem 1996; 271: 6746–6751.

    Google Scholar 

  60. Zamzami N, Marchetti P, Castedo M, et al. Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis. FEBS Lett 1996; 384: 53–57.

    Google Scholar 

  61. Waring P, Beaver J. Cyclosporin A rescues thymocytes from apoptosis induced by very low concentrations of thapsigargin: Effects on mitochondrial function. Exp Cell Res 1996; 227: 264–276.

    Google Scholar 

  62. Scarlett JL, Murphy MP. Release of apoptogenic proteins from the mitochondrial intermembrane space during the mitochondrial permeability transition. FEBS Lett 1997; 418: 282–286.

    Google Scholar 

  63. Jürgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC. Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA 1998; 95: 4997–5002.

    Google Scholar 

  64. Pastorino JG, Tafani M, Rothman RJ, Marcineviciute A, Hoek JB, Farber JL. Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J Biol Chem 1999; 274: 31734–31739.

    Google Scholar 

  65. Marzo I, Brenner C, Zamzami N, et al. The permeability transition pore complex: A target for apoptosis regulation by caspases and Bcl-2-related proteins. J Exp Med 1998; 187: 1261–1271.

    Google Scholar 

  66. Eskes R, Antonsson B, Osen-Sand A, et al. Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. J Cell Biol 1998; 143: 217–224.

    Google Scholar 

  67. De Giorgi F, Lartigue L, Bauer MKA, et al. The permeability transition pore signals apoptosis by directing Bax translocation and multimerization. FASEB J 2002: 16: 607–609.

    Google Scholar 

  68. Antonsson B, Montessuit S, Lauper S, Eskes R, Martinou J-C. Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J 2000; 345: 271–278.

    Google Scholar 

  69. Martinou J-C, Green DR. Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol 2001; 2: 63–67.

    Google Scholar 

  70. Marzo I, Brenner C, Zamzami N, et al. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 1998; 281: 2027–2031.

    Google Scholar 

  71. Shimizu S, Ide T, Yanagida T, Tsujimoto Y. Electrophysiological study of a novel large pore formed by bax and the voltagedependent anion channel that is permeable to cytochrome c. J Biol Chem 2000; 275: 12321–12325.

    Google Scholar 

  72. Saito M, Korsmeyer SJ, Schlesinger PH. BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat Cell Biol 2000; 2: 553–555.

    Google Scholar 

  73. Pavlov EV, Priault M, Pietkiewicz D, et al. A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and Bax expression in yeast. J Cell Biol 2001; 155: 725–731.

    Google Scholar 

  74. Vander Heiden MG, Chandel NS, Schumacker PT, Thompson CB. Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrialATP/ADPexchange. Mol Cell 1999; 3: 159–167.

    Google Scholar 

  75. Scarlett JL, Sheard PW, Hughes G, Ledgerwood EC, Ku H-H, Murphy MP. Changes in mitochondrial membrane potential during staurosporine-induced apoptosis in Jurkat cells. FEBS Lett 2000; 475: 267–272.

    Google Scholar 

  76. Grubb DR, Ly JD, Vaillant F, Johnson KL, Lawen A. Mitochondrial cytochrome c release is caspase-dependent and does not involve mitochondrial permeability transition in didemnin B-induced apoptosis. Oncogene 2001; 20: 4085–4094.

    Google Scholar 

  77. Cohen GM. Caspases: The executioners of apoptosis. Biochem J 1997; 326: 1–16.

    Google Scholar 

  78. Petit PX, Lecoeur H, Zorn E, Dauguet C, Mignotte B, Gougeon ML. Alterations in mitochondrial structure and function are early events of dexamethasone-induced thymocyte apoptosis. J Cell Biol 1995; 130: 157–167.

    Google Scholar 

  79. Barbu A, Welsh N, Saldeen J. Cytokine-induced apoptosis and necrosis are preceded by disruption of the mitochondrial membrane potential (ΔΨm) in pancreatic RINm5F cells: Prevention by Bcl-2. Mol Cell Endo 2002; 190: 75–82.

    Google Scholar 

  80. Kim T-S, Jeong D-W, Yun BY, Kim IY. Dysfunction of rat liver mitochondria by selenite: Induction of mitochondrial permeability transition through thiol-oxidation. Biochem Biophys Res Commun 2002; 294: 1130–1137.

    Google Scholar 

  81. Schempp CM, Kirkin V, Simon-Haarhaus B, et al. Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John’s wort that acts by induction of apoptosis. Oncogene 2002; 21: 1242–1250.

    Google Scholar 

  82. Macho A, Lucena C, Calzado MA, et al. Phorboid 20-homovanillates induce apoptosis through a VR1-independent mechanism. Chem Biol 2000; 7: 483–492.

    Google Scholar 

  83. Macho A, Calzado MA, Muñoz-Blanco J, et al. Selective induction of apoptosis by capsaicin in transformed cells: The role of reactive oxygen species and calcium. Cell Death Differ 1999; 6: 155–165.

    Google Scholar 

  84. Macho A, Blazquez MV, Navas P, Munoz E. Induction of apoptosis by vanilloid compounds does not require de novo gene transcription and activator protein 1 activity. Cell Growth Differ 1998; 9: 277–286.

    Google Scholar 

  85. Wolvetang EJ, Larm JA, Moutsoulas P, Lawen A. Apoptosis induced by inhibitors of the plasma membrane NADHoxidase involves Bcl-2 and calcineurin. Cell Growth Differ 1996; 7: 1315–1325.

    Google Scholar 

  86. Vieira HLA, Boya P, Cohen I, et al. Cell permeable BH3-peptides overcome the cytoprotective effect of Bcl-2 and Bcl-XL. Oncogene 2002; 21: 1963–1977.

    Google Scholar 

  87. Arnoult D, Tatischeff I, Estaquier J, et al. On the evolutionary conservation of the cell death pathway: Mitochondrial release of an apoptosis-inducing factor during Dictyostelium discoideum cell death. Mol Biol Cell 2001; 12: 3016–3030.

    Google Scholar 

  88. Saviani EE, Orsi CH, Oliveira JFP, Pinto-Maglio CAF, Salgado I. Participation of the mitochondrial permeability transition pore in nitric oxide-induced plant cell death. FEBS Lett 2002; 510: 136–140.

    Google Scholar 

  89. Yu X-H, Perdue TD, Heimer YM, Jones AM. Mitochondrial involvement in tracheary element programmed cell death. Cell Death Differ 2002; 9: 189–198.

    Google Scholar 

  90. Yang J-H, Gross RL, Basinger SF, Wu SM. Apoptotic cell death of cultured salamander photoreceptors induced by cccp: CsA-insensitive mitochondrial permeability transition. J Cell Sci 2001; 114: 1655–1664.

    Google Scholar 

  91. Mahyar-Roemer M, Katsen A, Mestres P, Roemer K. Resveratrol induces colon tumor cell apoptosis independently of p53 and preceded by epithelial differentiation, mitochondrial proliferation and membrane potential collapse. Int J Cancer 2001; 94: 615–622.

    Google Scholar 

  92. Marzo I, Pérez-Galán P, Giraldo P, Rubio-Félix D, Anel A, Naval J. Cladribine induces apoptosis in human leukaemia cells by caspase-dependent and-independent pathways acting on mitochondria. Biochem J 2001; 359: 537–546.

    Google Scholar 

  93. Damdimopoulos AE, Miranda-Vizuete A, Pelto-Huikko M, Gustafsson J-Å, Spyrou G. Human mitochondrial thioredoxin. Involvement in mitochondrial membrane potential and cell death. J Biol Chem 2002; 277: 33249–33257.

    Google Scholar 

  94. Sokolove PM, Shinaberry RG. Na+-independent release of Ca2+ from rat heart mitochondria. Induction by adriamycin aglycone. Biochem Pharmacol 1988; 37: 803–812.

    Google Scholar 

  95. Kruman I, Guo Q, Mattson MP. Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells. J Neurosci Res 1998; 51: 293–308.

    Google Scholar 

  96. Kruman II, Mattson MP. Pivotal role of mitochondrial calcium uptake in neural cell apoptosis and necrosis. J Neurochem 1999; 72: 529–540.

    Google Scholar 

  97. Koya RC, Fujita H, Shimizu S, et al. Gelsolin inhibits apoptosis by blocking mitochondrial membrane potential loss and cytochrome c release. J Biol Chem 2000; 275: 15343–15349.

    Google Scholar 

  98. Lemasters JJ, Nieminen A-L, Qian T, et al. The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1998; 1366: 177–196.

    Google Scholar 

  99. Lemasters JJ, Nieminen A-L. Mitochondrial oxygen radical formation during reductive and oxidative stress to intact hepatocytes. Biosci Rep 1997; 17: 281–291.

    Google Scholar 

  100. Lawen A. Biosynthesis and mechanism of action of cyclosporins. Prog Med Chem 1996; 33: 53–97.

    Google Scholar 

  101. Thomas DA, Scorrano L, Putcha GV, Korsmeyer SJ, Ley TJ. Granzyme B can cause mitochondrial depolarization and cell death in the absence of BID, BAX, and BAK. Proc Natl Acad Sci USA 2001; 98: 14985–14990.

    Google Scholar 

  102. Larochette N, Decaudin D, Jacotot E, et al. Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. Exp Cell Res 1999; 249: 413–421.

    Google Scholar 

  103. Pardo J, Pérez-Galán P, Gamen S, et al. A Role of the mitochondrial apoptosis-inducing factor in granulysin-induced apoptosis. J Immunol 2001; 167: 1222–1229.

    Google Scholar 

  104. Cossarizza A, Kalashnikova G, Grassilli E, et al. Mitochondrial modifications during rat thymocyte apoptosis: A study at the single cell level. Exp Cell Res 1994; 214: 323–330.

    Google Scholar 

  105. Hishita T, Tada-Oikawa S, Tohyama K, et al. Caspase-3 activation by lysosomal enzymes in cytochrome c-independent apoptosis in myelodysplastic syndrome-derived cell line P39. Cancer Res 2001; 61: 2878–2884.

    Google Scholar 

  106. Karpinich NO, Tafani M, Rothman RJ, Russo MA, Farber JL. The course of etoposide-induced apoptosis from damage to DNA and p53 activation to mitochondrial release of cytochrome c. J Biol Chem 2002; 277: 16547–16552.

    Google Scholar 

  107. Denning MF, Wang Y, Tibudan S, Alkan S, Nickoloff BJ, Qin J-Z. Caspase activation and disruption of mitochondrial membrane potential during UV radiation-induced apoptosis of human keratinocytes requires activation of protein kinase C. Cell Death Differ 2002; 9: 40–52.

    Google Scholar 

  108. Nopp A, Lundahl J, Stridh H. Caspase activation in the absence of mitochondrial changes in granulocyte apoptosis. Clin Exp Immunol 2002; 128: 267–274.

    Google Scholar 

  109. Oubrahim H, Stadtman ER, Chock PB. Mitochondria play no roles in Mn(II)-induced apoptosis in HeLa cells. Proc Natl Acad Sci USA 2001; 98: 9505–9510.

    Google Scholar 

  110. Finucane DM, Waterhouse NJ, Amarante-Mendes GP, Cotter TG, Green DR. Collapse of the inner mitochondrial transmembrane potential is not required for apoptosis of HL60 cells. Exp Cell Res 1999; 251: 166–174.

    Google Scholar 

  111. Marchetti P, Susin SA, Decaudin D, et al. Apoptosis-associated derangement of mitochondrial function in cells lacking mitochondrial DNA. Cancer Res 1996; 56: 2033–2038.

    Google Scholar 

  112. Jacobson MD, Burne JF, King MP, Miyashita T, Reed JC, Raff MC. Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA. Nature 1993; 361: 365–369.

    Google Scholar 

  113. Gamen S, Anel A, Montoya J, Marzo I, Piñeiro A, Naval J. mtDNA-depleted U937 cells are sensitive to TNF and Fasmediated cytotoxicity. FEBS Lett 1995; 376: 15–18.

    Google Scholar 

  114. Pastorino JG, Chen S-T, Tafani M, Snyder JW, Farber JL. The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem 1998; 273: 7770–7775.

    Google Scholar 

  115. Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR. Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by BclxL. J Biol Chem 1999; 274: 2225–2233.

    Google Scholar 

  116. Susin SA, Zamzami N, Castedo M, et al. The central executioner of apoptosis: Multiple connections between protease activation and mitochondria in Fas/APO-1/CD95-and ceramide-induced apoptosis. J Exp Med 1997; 186: 25–37.

    Google Scholar 

  117. Gamen S, Anel A, Pérez-Galán P, et al. Doxorubicin treatment activates a Z-VAD-sensitive caspase, which causes ΔΨm loss, caspase-9 activity, and apoptosis in Jurkat cells. Exp Cell Res 2000; 258: 223–235.

    Google Scholar 

  118. von Ahsen O, Renken C, Perkins G, Kluck RM, Bossy-Wetzel E, Newmeyer DD. Preservation of mitochondrial structure and function after Bid-or Bax-mediated cytochrome c release. J Cell Biol 2000; 150: 1027–1036.

    Google Scholar 

  119. 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: 156–162.

    Google Scholar 

  120. Martinou J-C, Desagher S, Antonsson B. Cytochrome c release from mitochondria: All or nothing. Nat Cell Biol 2000; 2: E41–E43.

    Google Scholar 

  121. van Loo G, Saelens X, van Gurp M, MacFarlane M, Martin SJ, Vandenabeele P. The role of mitochondrial factors in apoptosis: A Russian roulette with more than one bullet. Cell Death Differ 2002; 9: 1031–1042.

    Google Scholar 

  122. Waterhouse NJ, Ricci J-E, Green DR. And all of a sudden it’s over: Mitochondrial outer-membrane permeabilization in apoptosis. Biochimie 2002; 84: 113–121.

    Google Scholar 

  123. Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 1997; 275: 1129–1132.

    Google Scholar 

  124. Petit PX, Goubern M, Diolez P, Susin SA, Zamzami N, Kroemer G. Disruption of the outer mitochondrial membrane as a result of large amplitude swelling: The impact of irreversible permeability transition. FEBS Lett 1998; 426: 111–116.

    Google Scholar 

  125. Krajewski S, Krajewska M, Ellerby LM, et al. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci USA 1999; 96: 5752–5757.

    Google Scholar 

  126. Mignotte B, Vayssière J-L. Mitochondria and apoptosis. Eur J Biochem 1998; 252: 1–15.

    Google Scholar 

  127. Ding W-X, Shen H-M, Ong C-N. Calpain activation after mitochondrial permeability transition in microcystin-induced cell death in rat hepatocytes. Biochem Biophys Res Commun 2002; 291: 321–331.

    Google Scholar 

  128. Brustovetsky N, Brustovetsky T, Jemmerson R, Dubinsky JM. Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. J Neurochem 2002; 80: 207–218.

    Google Scholar 

  129. Heiskanen KM, Bhat MB, Wang H-W, Ma J, Nieminen AL. Mitochondrial depolarization accompanies cytochrome c release during apoptosis in PC6 cells. J Biol Chem 1999; 274: 5654–5658.

    Google Scholar 

  130. Yoshino T, Kishi H, Nagata T, Tsukada K, Saito S, Muraguchi A. Differential involvement of p38 MAP kinase pathway and Bax translocation in the mitochondria-mediated cell death in TCR-and dexamethasone-stimulated thymocytes. Eur J Immunol 2001; 31: 2702–2708.

    Google Scholar 

  131. Zhuang J, Dinsdale D, Cohen GM. Apoptosis, in human monocytic THP.1 cells, results in the release of cytochrome c from mitochondria prior to their ultracondensation, formation of outer membrane discontinuities and reduction in inner membrane potential. Cell Death Differ 1998; 5: 953–962.

    Google Scholar 

  132. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 1997; 275: 1132–1136.

    Google Scholar 

  133. Polster BM, Kinnally KW, Fiskum G. BH3 death domain peptide induces cell type-selective mitochondrial outer membrane permeability. J Biol Chem 2001; 276: 37887–37894.

    Google Scholar 

  134. Shimizu S, Tsujimoto Y. Proapoptotic BH3-only Bcl-2 family members induce cytochrome c release, but not mitochondrial membrane potential loss, and do not directly modulate voltage-dependent anion channel activity. Proc Natl Acad Sci USA 2000; 97: 577–582.

    Google Scholar 

  135. Madesh M, Antonsson B, Srinivasula SM, Alnemri ES, Hajnóczky G. Rapid kinetics of tBid-induced cytochrome c and Smac/DIABLO release and mitochondrial depolarization. J Biol Chem 2002; 277: 5651–5659.

    Google Scholar 

  136. Mootha VK, Wei MC, Buttle KF, et al. A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c. EMBO J 2001; 20: 661–671.

    Google Scholar 

  137. Lim MLR, Minamikawa T, Nagley P. The protonophore CCCP induces mitochondrial permeability transition without cytochrome c release in human osteosarcoma cells. FEBS Lett 2001; 251: 1–6.

    Google Scholar 

  138. Degenhardt K, Sundararajan R, Lindsten T, Thompson C, White E. Bax and Bak independently promote cytochrome c release from mitochondria. J Biol Chem 2002; 277: 14127–14134.

    Google Scholar 

  139. Germain M, Mathai JP, Shore GC. BH3-only Bik functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria. J Biol Chem 2002; 277: 18053–18060.

    Google Scholar 

  140. Chen Q, Gong B, Almasan A. Distinct stages of cytochrome c release from mitochondria: Evidence for a feedback amplification loop linking caspase activation to mitochondrial dysfunction in genotoxic stress induced apoptosis. Cell Death Diff 2000; 7: 227–233.

    Google Scholar 

  141. Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S. Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci USA 2002; 99: 1259–1263.

    Google Scholar 

  142. Tuominen EKJ, Zhu K, Wallace CJA, et al. ATP induces a conformational change in lipid-bound cytochrome c. J Biol Chem 2001; 276: 19356–19362.

    Google Scholar 

  143. Susin SA, Lorenzo HK, Zamzami N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999; 397: 441–446.

    Google Scholar 

  144. Daugas E, Susin SA, Zamzami N, et al. Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J 2000; 14: 729–739.

    Google Scholar 

  145. Fulda S, Meyer E, Debatin K-M. Inhibition of TRAILinduced apoptosis by Bcl-2 overexpression. Oncogene 2002; 21: 2283–2294.

    Google Scholar 

  146. Joseph B, Marchetti P, Formstecher P, Kroemer G, Lewensohn R, Zhivotovsky B. Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to conventional treatment. Oncogene 2002; 21: 65–77.

    Google Scholar 

  147. Shapiro HM. Cell membrane potential analysis. Methods Cell Biol 1994; 41: 121–133.

    Google Scholar 

  148. Smiley ST, Reers M, Mottola-Hartshorn C, et al. Intracellular heterogeneity in mitochondrial membrane potentials revealed by J-aggregate-forming lipophilic cation JC-1. Proc Natl Acad Sci USA 1991; 88: 3671–3675.

    Google Scholar 

  149. Salvioli S, Ardizzoni A, Franceschi C, Cossarizza A. JC-1, but not DiOC6(3) or rhodamine 123, is a reliable fluorescent probe to assess ΔΨ changes in intact cells: Implications for studies on mitochondrial functionality during apoptosis. FEBS Lett 1997; 411: 77–82.

    Google Scholar 

  150. Reers M, Smith TW, Chen LB. J-aggregate formation of a carbocyanine as a quantitative fluorescent indicator of membrane potential. Biochemistry 1991; 30: 4480–4486.

    Google Scholar 

  151. Mathur A, Hong Y, Kemp BK, Barrientos AA, Erusalimsky JD. Evaluation of fluorescent dyes for the detection of mitochondrial membrane potential changes in cultured cardiomyo-cytes. Cardiovasc Res 2000; 46: 126–138.

    Google Scholar 

  152. Rottenberg H, Wu S. Quantitative assay by flow cytometry of the mitochondrial membrane potential in intact cells. Biochim Biophys Acta 1998; 1404: 393–404.

    Google Scholar 

  153. Bortner CD, Cidlowski JA. Caspase independent/dependent regulation of K+, cell shrinkage, and mitochondrial membrane potential during lymphocyte apoptosis. J Biol Chem 1999; 274: 21953–21962.

    Google Scholar 

  154. Dietze EC, Caldwell LE, Grupin SL, Mancini M, Seewaldt VL. Tamoxifen but not 4-hydroxytamoxifen initiates apoptosis in p53(-) normal human mammary epithelial cells by inducing mitochondrial depolarization. J Biol Chem 2001; 276: 5384–5394.

    Google Scholar 

  155. Loew LM. Measuring membrane potential in single cells with confocal microscopy. In: Celis JE, ed. Cell Biology: A Laboratory Handbook, 2nd Ed. Sydney: Academic Press, 1998: 8; 195–209.

    Google Scholar 

  156. Scaduto RC Jr, Grotyohann LW. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 1999; 76: 469–477.

    Google Scholar 

  157. Emaus RK, Grunwald R, Lemasters JJ. Rhodamine 123 as a probe of transmembrane potential in isolated rat-liver mitochondria: Spectral and metabolic properties. Biochim Biophys Acta 1986; 850: 436–448.

    Google Scholar 

  158. Farkas DL, Wei MD, Febbroriello P, Carson JH, Loew LM. Simultaneous imaging of cell and mitochondrial membrane potentials. Biophys J 1989; 56: 1053–1069.

    Google Scholar 

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  1. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Building 13D, Melbourne, 3800, Australia

    J. D. Ly, D. R. Grubb & A. Lawen

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Ly, J.D., Grubb, D.R. & Lawen, A. The mitochondrial membrane potential (Δψm) in apoptosis; an update. Apoptosis 8, 115–128 (2003). https://doi.org/10.1023/A:1022945107762

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