Abstract
Mitochondria control whether a cell lives or dies. The role mitochondria play in deciding the fate of a cell was first identified in the mid-1990s, because mitochondria-enriched fractions were found to be necessary for activation of death proteases, the caspases, in a cell-free model of apoptotic cell death. Mitochondrial involvement in apoptosis was subsequently shown to be regulated by Bcl-2, a protein that was known to contribute to cancer in specific circumstances. The important role of mitochondria in promoting caspase activation has therefore been a major focus of apoptosis research; however, it is also clear that mitochondria contribute to cell death by caspase-independent mechanisms. In this review, we will highlight recent findings and discuss the mechanism underlying the mitochondrial control of apoptosis and caspase-independent cell death.
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References
Youle R, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59
Vaux DL, Cory S, Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335:440–442
Hengartner MO, Ellis RE, Horvitz HR (1992) Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356:494–499
Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G, Korsmeyer SJ, MacGregor GR, Thompson CB (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6:1389–1399
Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163
Fu N, Sukumaran S, Kerk S, Yu V (2009) Baxβ: a constitutively active human Bax isoform that is under tight regulatory control by the proteasomal degradation mechanism. Mol Cell 33:15–29
Dewson G, Kratina T, Sim H, Puthalakath H, Adams J, Colman P, Kluck R (2008) To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3: groove interactions. Mol Cell 30:369–380
Chipuk J, Green D (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18:157–164
Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC (2007) Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315:856–859
Lovell J, Billen L, Bindner S, Shamasdin A, Fradin C, Leber B, Andrews D (2008) Membrane binding by tBid Initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 135:1074–1084
Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303:1010–1014
Leu JI, Dumont P, Hafey M, Murphy ME, George DL (2004) Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 6:443–450
Gavathiotis E, Suzuki M, Davis M, Pitter K, Bird G, Katz S, Tu H, Kim H, Cheng EH, Tjandra N, Walensky L (2008) BAX activation is initiated at a novel interaction site. Nature 455:1076–1081
Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N (2000) Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288:1053–1058
Nakano K, Vousden KH (2001) PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 7:683–694
Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ (2000) Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 10:1201–1204
Puthalakath H, O’reilly L, Gunn P, Lee L, Kelly P, Huntington N, Hughes P, Michalak E, Mckimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337–1349
Warr MR, Shore GC (2008) Unique biology of Mcl-1: therapeutic opportunities in cancer. Curr Mol Med 8:138–147
Wendel H, Silva R, Malina A, Mills J, Zhu H, Ueda T, Watanabe-Fukunaga R, Fukunaga R, Teruya-Feldstein J, Pelletier J, Lowe S (2007) Dissecting eIF4E action in tumorigenesis. Genes Dev 21:3232–3237
Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006) Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21:749–760
Sherrill KW, Byrd MP, Van Eden ME, Lloyd RE (2004) BCL-2 translation is mediated via internal ribosome entry during cell stress. J Biol Chem 279:29066–29074
Braunstein S, Karpisheva K, Pola C, Goldberg J, Hochman T, Yee H, Cangiarella J, Arju R, Formenti SC, Schneider RJ (2007) A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. Mol Cell 28:501–512
Pradelli LA, Beneteau M, Chauvin C, Jacquin MA, Marchetti S, Munoz-Pinedo C, Auberger P, Pende M, Ricci JE (2009) Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation. Oncogene (in press)
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70
Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A (2007) Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 117:112–121
Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M (2006) Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10:375–388
Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A (2007) BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 12:171–185
Roy S, Madesh M, Davies E, Antonsson B, Danial N, Hajnóczky G (2009) Bad targets the permeability transition pore independent of Bax or Bak to switch between Ca2+-dependent cell survival and death. Mol Cell 33:377–388
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
Du C, Fang M, Li Y, Li L, Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102:33–42
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102:43–53
Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG (2004) A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science 305:1471–1474
Chauhan D, Neri P, Velankar M, Podar K, Hideshima T, Fulciniti M, Tassone P, Raje N, Mitsiades C, Mitsiades N, Richardson P, Zawel L, Tran M, Munshi N, Anderson KC (2007) Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). Blood 109:1220–1227
Wu H, Tschopp J, Lin SC (2007) Smac mimetics and TNFalpha: a dangerous liaison? Cell 131:655–658
Verhagen AM, Kratina TK, Hawkins CJ, Silke J, Ekert PG, Vaux DL (2007) Identification of mammalian mitochondrial proteins that interact with IAPs via N-terminal IAP binding motifs. Cell Death Differ 14:348–357
Waterhouse NJ, Goldstein JC, von Ahsen O, Schuler M, Newmeyer DD, Green DR (2001) Cytochrome c maintains mitochondrial transmembrane potential and ATP generation after outer mitochondrial membrane permeabilization during the apoptotic process. J Cell Biol 153:319–328
Ricci JE, Munoz-Pinedo C, Fitzgerald P, Bailly-Maitre B, Perkins GA, Yadava N, Scheffler IE, Ellisman MH, Green DR (2004) Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117:773–786
Denmeade SR, Lin XS, Tombal B, Isaacs JT (1999) Inhibition of caspase activity does not prevent the signaling phase of apoptosis in prostate cancer cells. Prostate 39:269–279
Okuno S, Shimizu S, Ito T, Nomura M, Hamada E, Tsujimoto Y, Matsuda H (1998) Bcl-2 prevents caspase-independent cell death. J Biol Chem 273:34272–34277
Wilkinson JC, Cepero E, Boise LH, Duckett CS (2004) Upstream regulatory role for XIAP in receptor-mediated apoptosis. Mol Cell Biol 24:7003–7014
Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94:339–352
Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325–337
Li K, Li Y, Shelton JM, Richardson JA, Spencer E, Chen ZJ, Wang X, Williams RS (2000) Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell 101:389–399
Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94:739–750
Chautan M, Chazal G, Cecconi F, Gruss P, Golstein P (1999) Interdigital cell death can occur through a necrotic and caspase- independent pathway. Curr Biol 9:967–970
Tait SW, Green DR (2008) Caspase-independent cell death: leaving the set without the final cut. Oncogene 27:6452–6461
Li LY, Luo X, Wang X (2001) Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95–99
Zhang J, Dong M, Li L, Fan Y, Pathre P, Dong J, Lou D, Wells JM, Olivares-Villagomez D, Van Kaer L, Wang X, Xu M (2003) Endonuclease G is required for early embryogenesis and normal apoptosis in mice. Proc Natl Acad Sci USA 100:15782–15787
David KK, Sasaki M, Yu SW, Dawson TM, Dawson VL (2006) EndoG is dispensable in embryogenesis and apoptosis. Cell Death Differ 13:1147–1155
Irvine RA, Adachi N, Shibata DK, Cassell GD, Yu K, Karanjawala ZE, Hsieh CL, Lieber MR (2005) Generation and characterization of endonuclease G null mice. Mol Cell Biol 25:294–302
Susin SA, Zamzami N, Castedo M, Hirsch T, Marchetti P, Macho A, Daugas E, Geuskens M, Kroemer G (1996) Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J Exp Med 184:1331–1341
Niikura Y, Dixit A, Scott R, Perkins G, Kitagawa K (2007) BUB1 mediation of caspase-independent mitotic death determines cell fate. J Cell Biol 178:283–296
Cande C, Vahsen N, Kouranti I, Schmitt E, Daugas E, Spahr C, Luban J, Kroemer RT, Giordanetto F, Garrido C, Penninger JM, Kroemer G (2004) AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Oncogene 23:1514–1521
Brown D, Yu BD, Joza N, Benit P, Meneses J, Firpo M, Rustin P, Penninger JM, Martin GR (2006) Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal. Proc Natl Acad Sci USA 103:9918–9923
Cheung EC, Joza N, Steenaart NA, McClellan KA, Neuspiel M, McNamara S, MacLaurin JG, Rippstein P, Park DS, Shore GC, McBride HM, Penninger JM, Slack RS (2006) Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis. EMBO J 25:4061–4073
Vande Walle L, Lamkanfi M, Vandenabeele P (2008) The mitochondrial serine protease HtrA2/Omi: an overview. Cell Death Differ 15:453–460
Martins LM, Morrison A, Klupsch K, Fedele V, Moisoi N, Teismann P, Abuin A, Grau E, Geppert M, Livi GP, Creasy CL, Martin A, Hargreaves I, Heales SJ, Okada H, Brandner S, Schulz JB, Mak T, Downward J (2004) Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol Cell Biol 24:9848–9862
Moisoi N, Klupsch K, Fedele V, East P, Sharma S, Renton A, Plun-Favreau H, Edwards RE, Teismann P, Esposti MD, Morrison AD, Wood NW, Downward J, Martins LM (2009) Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ 16:449–464
Chao JR, Parganas E, Boyd K, Hong CY, Opferman JT, Ihle JN (2008) Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 452:98–102
Colell A, Ricci JE, Tait S, Milasta S, Maurer U, Bouchier-Hayes L, Fitzgerald P, Guio-Carrion A, Waterhouse NJ, Li CW, Mari B, Barbry P, Newmeyer DD, Beere HM, Green DR (2007) GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell 129:983–997
Colell A, Green DR, Ricci JE (2009) Novel roles for GAPDH in cell death and carcinogenesis. Cell Death Differ 16:1573–1581
Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C, Lowe SW (2001) Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409:207–211
Jia L, Srinivasula SM, Liu FT, Newland AC, Fernandes-Alnemri T, Alnemri ES, Kelsey SM (2001) Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemic cells. Blood 98:414–421
Leo C, Horn LC, Rauscher C, Hentschel B, Richter CE, Schutz A, Leo CP, Hockel M (2007) Lack of apoptotic protease activating factor-1 expression and resistance to hypoxia-induced apoptosis in cervical cancer. Clin Cancer Res 13:1149–1153
Zlobec I, Minoo P, Baker K, Haegert D, Khetani K, Tornillo L, Terracciano L, Jass JR, Lugli A (2007) Loss of APAF-1 expression is associated with tumour progression and adverse prognosis in colorectal cancer. Eur J Cancer 43:1101–1107
Tamm I, Richter S, Scholz F, Schmelz K, Oltersdorf D, Karawajew L, Schoch C, Haferlach T, Ludwig WD, Wuchter C (2004) XIAP expression correlates with monocytic differentiation in adult de novo AML: impact on prognosis. Hematol J 5:489–495
Li M, Song T, Yin ZF, Na YQ (2007) XIAP as a prognostic marker of early recurrence of nonmuscular invasive bladder cancer. Chin Med J (Engl) 120:469–473
Hong SW, Kim CJ, Park WS, Shin JS, Lee SD, Ko SG, Jung SI, Park IC, An SK, Lee WK, Lee WJ, Jin DH, Lee MS (2009) p34SEI-1 inhibits apoptosis through the stabilization of the X-linked inhibitor of apoptosis protein: p34SEI-1 as a novel target for anti-breast cancer strategies. Cancer Res 69:741–746
Deming PB, Schafer ZT, Tashker JS, Potts MB, Deshmukh M, Kornbluth S (2004) Bcr-Abl-mediated protection from apoptosis downstream of mitochondrial cytochrome c release. Mol Cell Biol 24:10289–10299
Kurokawa M, Zhao C, Reya T, Kornbluth S (2008) Inhibition of apoptosome formation by suppression of Hsp90beta phosphorylation in tyrosine kinase-induced leukemias. Mol Cell Biol 28:5494–5506
Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E, Tanaka H, Yui Y, Watanabe M, Matsubara H, Mizushima Y, Hiraumi Y, Kawata E, Yoshikawa T, Maekawa T, Nakahata T, Adachi S (2008) The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ 15:1712–1722
Okada M, Adachi S, Imai T, Watanabe K, Toyokuni SY, Ueno M, Zervos AS, Kroemer G, Nakahata T (2004) A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity. Blood 103:2299–2307
Apperley JF (2007) Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 8:1018–1029
Lavallard VJ, Pradelli LA, Paul A, Beneteau M, Jacquel A, Auberger P, Ricci JE (2009) Modulation of caspase-independent cell death leads to resensitization of imatinib mesylate-resistant cells. Cancer Res 69:3013–3020
Hulleman E, Kazemier KM, Holleman A, VanderWeele DJ, Rudin CM, Broekhuis MJ, Evans WE, Pieters R, Den Boer ML (2009) Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells. Blood 113:2014–2021
Acknowledgments
We would like to thank Dr. Waterhouse (Mater Medical Research Institute, Brisbane, Australia) for critical reading of this manuscript. This work was supported in part by grants from Association pour la Recherche sur le Cancer (ARC), l’Agence Nationale de la Recherche (ref ANR-09-JCJC-0003-01), la Fondation de France and Région Provence-Alpes-Cote-d’Azur. J-E.R. is a recipient of a contrat d’interface INSERM-CHU de Nice.
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Pradelli, L.A., Bénéteau, M. & Ricci, JE. Mitochondrial control of caspase-dependent and -independent cell death. Cell. Mol. Life Sci. 67, 1589–1597 (2010). https://doi.org/10.1007/s00018-010-0285-y
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DOI: https://doi.org/10.1007/s00018-010-0285-y