Abstract
Here we review recent observations indicating the existence of redundant cell death mechanisms. We speculate that this redundancy reflects a particular evolutionary history for cellular demise. Autophagic or apoptotic elements might have been added to a primordial death mechanism, initially improving cell dismantling and later acquiring the ability to act themselves as death effectors. The resulting redundancy of cell death mechanisms has pathophysiological implications.
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Abbreviations
- AIF:
-
apoptosis inducing factor
- Cyt c:
-
cytochrome c
References
Kerr JFR, Wyllie AH and Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26: 239–257
Clarke PGH and Clarke S (1995) Historic apoptosis. Nature 378: 230
Majno G and Joris I (1995) Apoptosis, oncosis, and necrosis. An overview of cell death. Am. J. Pathol. 146: 3–15
Bursch W (2001) The autophagosomal–lysosomal compartment in programmed cell death. Cell Death Differ. 8: 569–581
Leist M and Jaattela M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat. Rev. Mol. Cell Biol. 2: 589–598
Sperandio S, Poksay K, De Belle I, Lafuente MJ, Liu B, Nasir J and Bredesen DE (2004) Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Cell Death Differ. 11: 1066–1075
Lemasters JJ (1999) V. Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis. Am. J. Physiol. 276 (1 Part 1): G1–G6
Lee CY and Baehrecke EH. (2001) Steroid regulation of autophagic programmed cell death during development. Development 128: 1443–1455
Martin DN and Baehrecke EH (2004) Caspases function in autophagic programmed cell death in Drosophila. Development. 131: 275–284
Levine B and Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell. 6: 463–477
Leist M, Single B, Castoldi AF, Kühnle S and Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J. Exp. Med. 185: 1481–1486
Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A and Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391: 43–50
Sebbagh M, Renvoize C, Hamelin J, Riche N, Bertoglio J and Breard J (2001) Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat. Cell Biol. 3: 346–352
Savill J, Dransfield I, Gregory C and Haslett C (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2: 965–975
Reddien PW and Horvitz HR (2004) The engulfment process of programmed cell death in Caenorhabditis elegans. Annu. Rev. Cell Dev. Biol. 20: 193–221
Ellis HM and Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell. 44: 817–829
Vercammen D, Brouckaert G, Denecker G, Van de Craen M, Declercq W, Fiers W and Vandenabeele P (1998) Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. J. Exp. Med. 188: 919–930
Kawahara A, Ohsawa Y, Matsumura H, Uchiyama Y and Nagata S (1998) Caspase-independent cell killing by fas-associated protein with death domain. J. Cell Biol. 143: 1353–1360
Matsumura H, Shimizu Y, Ohsawa Y, Kawahara A, Uchiyama Y and Nagata S (2000) Necrotic death pathway in fas receptor signaling. J. Cell Biol. 151: 1247–1256
Holler N, Zaru R, Micheau O, Thome M, Attinge A, Valitutti S, Bodmer JL, Schneider P, Seed B and Tschopp J (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1: 489–495
Van den Berghe T, Van Loo G, Saelens X, Van Gurp M, Brouckaert G, Kalai M, Declercq W and Vandenabeele P (2004) Differential signaling to apoptotic and necrotic cell death by Fas-associated death domain protein FADD. J. Biol. Chem. 279: 7925–7933
Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH and Lenardo MJ (2004) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304: 1500–1502
Hirsch T, Marchetti P, Susin SA, Dallaporta B, Zamzami N, Marzo I, Geuskens M and Kroemer G (1997) The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death. Oncogene 15: 1573–1582
Xue L, Fletcher GC and Tolkovsky AM (2001) Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis. Curr. Biol. 6: 361–365
Saeki K, Yuo A, Okuma E, Yazaki Y, Susin SA, Kroemer G and Takaku F (2000) Bcl-2 down-regulation causes autophagy in a caspase-independent manner in human leukemic HL60 cells. Cell Death Differ. 7: 1263–1269
Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y and Kondo S (2004) Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res. 64: 4286–4293
Zong WX, Ditsworth D, Bauer DE, Wang ZQ and Thompson CB (2004) Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 18: 1272–1282
Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, Korsmeyer SJ and Tsujimoto Y (2004) A role of Bcl-2 family of proteins in non-apoptotic programmed cell death dependent on autophagy genes. Nat. Cell Biol. 6: 1221–1228
Boya P, Gonzalez-Polo R-A, Casares N, Perfettini J-L, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Pierron G, Ohsumi Y, Codogno P and Kroemer G (2005) Inhibition of macroautophagy triggers apoptosis. Mol. Cell. Biol. 25: 1025–1040
Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA and Gruss P (1998) Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94: 727–737
Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM and Mak TW (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94: 739–750
Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P and Flavell RA (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94: 325–337
Kuida K, Zheng TS, Na SQ, Kuan CY, Yang D, Karasuyama H, Rakic P and Flavell RA (1996) Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384: 368–372
Chautan M, Chazal G, Cecconi F, Gruss P and Golstein P (1999) Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr. Biol. 9: 967–970
Shao Y, Gao Z, Marks PA and Jiang X (2004) Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc. Natl. Acad. Sci. USA 101: 18030–18035
Oppenheim RW, Flavell RA, Vinsant S, Prevette D, Kuan CY and Rakic P (2001) Programmed cell death of developing mammalian neurons after genetic deletion of caspases. J. Neurosci. 21: 4752–4760
Yaginuma H, Shiraiwa N, Shimada T, Nishiyama K, Hong J, Wang S, Momoi T, Uchiyama Y and Oppenheim RW (2001) Caspase activity is involved in, but is dispensable for, early motoneuron death in the chick embryo cervical spinal cord. Mol. Cell Neurosci. 18: 168–182
Xu K, Tavernarakis N and Driscoll M (2001) Necrotic cell death in C. elegans requires the function of calreticulin and regulators of Ca(2+) release from the endoplasmic reticulum. Neuron 31: 957–971
Horvitz HR, Shaham S and Hengartner MO (1994) The genetics of programmed cell death in the nematode Caenorhabditis elegans. Cold Spring Harbor Symp. Quant. Biol. 59: 377–386
Cornillon S, Foa C, Davoust J, Buonavista N, Gross JD and Golstein P (1994) Programmed cell death in Dictyostelium. J. Cell Sci. 107: 2691–2704
Levraud J-P, Adam M, Luciani M-F, De Chastellier C, Blanton RL and Golstein P (2003) Dictyostelium cell death: early emergence and demise of highly polarized paddle cells. J. Cell Biol. 160: 1105–1114
Kosta A, Roisin-Bouffay C, Luciani MF, Otto GP, Kessin RH and Golstein P (2004) Autophagy gene disruption reveals a non-vacuolar cell death pathway in Dictyostelium. J. Biol. Chem. 279: 48404–48409
Inbal B, Bialik S, Sabanay I, Shani G and Kimchi A (2002) DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J. Cell Biol. 157: 455–468
Vercammen D, Beyaert R, Denecker G, Goossens V, Van Loo G, Declercq W, Grooten J, Fiers W and Vandenabeele P (1998) Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J. Exp. Med. 187: 1477–1485
Kim JS, Qian T and Lemasters JJ (2003) Mitochondrial permeability transition in the switch from necrotic to apoptotic cell death in ischemic rat hepatocytes. Gastroenterology. 124: 494–503
Koonin EV and Aravind L (2002) Origin and evolution of eukaryotic apoptosis: the bacterial connection. Cell Death Differ. 9: 394–404
Ameisen JC (2002) On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death Differ. 9: 367–393
Wissing S, Ludovico P, Herker E, Büttner S, Engelhardt SM, Decker T, Link A, Proksch A, Rodrigues F, Corte-Real M, Fröhlich K-U, Manns J, Candé C, Sigrist SJ, Kroemer G and Madeo F (2004) An AIF orthologue regulates apoptosis in yeast. J. Cell Biol. 166: 969–974
Cande C, Cecconi F, Dessen P and Kroemer G (2002) Apoptosis-inducing factor (AIF): key to the conserved caspase- independent pathways of cell death? J. Cell Sci. 115 (Part 24): 4727–4734
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH and Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 17: 1675–1687
Mehlen P and Thibert C (2004) Dependence receptors: between life and death. Cell Mol. Life Sci. 61: 1854–1866
Elmore SP, Qian T, Grissom SF and Lemasters JJ (2001) The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J. 15: 2286–2287
Tolkovsky AM, Xue L, Fletcher GC and Borutaite V (2002) Mitochondrial disappearance from cells: a clue to the role of autophagy in programmed cell death and disease? Biochimie 84: 233–240
Kissova II, Deffieu M, Manon S and Camougrand N (2004) Uth1p is involved in the autophagic degradation of mitochondria. J. Biol. Chem. 279: 39068–39074
Gavrieli Y, Sherman Y and Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119: 493–501
Garrido C and Kroemer G (2004) Life's smile, death's grin: vital functions of apoptosis-executing proteins. Curr. Opin. Cell Biol. 16: 639–646
Cauwels A, Janssen B, Waeytens A, Cuvelier C and Brouckaert P (2003) Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. Nat. Immunol. 4: 387–393
Mattson MP and Kroemer G (2003) Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol. Med. 9: 196–205
Knaapen MW, Davies MJ, De Bie M, Haven AJ, Martinet W and Kockx MM (2001) Apoptotic versus autophagic cell death in heart failure. Cardiovasc. Res. 51: 304–312
Hotchkiss RS, Chang K, Swanson PE, Tinsley KW, Hui JJ, Klender P, Xanthoudakis S, Roy S, Black C, Grimm E, Aspiotis R, Han Y, Nicholson DW and Karl IE (2000) Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat. Immunol. 1: 496–501
Jaattela M and Tschopp J (2003) Caspase-independent cell death in T lymphocytes. Nat. Immunol. 4: 416–423
Hoeppner DJ, Hengartner MO and Schnabel R (2001) Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature. 412: 202–206
Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N and Mallat M (2004) Microglia promote the death of developing Purkinje cells. Neuron 41: 535–547
Ekert PG, Silke J and Vaux DL (1999) Caspase inhibitors. Cell Death Differ. 6: 1081–1086
Griffin DE and Hardwick JM (1999) Perspective: virus infections and the death of neurons. Trends Microbiol. 7: 155–160
Mizushima N, Yamamoto A, Matsui M, Yoshimori T and Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell. 15: 1101–1111
Zhu C, Qiu L, Wang X, Hallin U, Cande C, Kroemer G, Hagberg H and Blomgren K (2003) Involvement of apoptosis-inducing factor in neuronal death after hypoxia–ischemia in the neonatal rat brain. J Neurochem. 86: 306–317
Green DR and Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305: 626–629
Stavrovskaya IG, Narayanan MV, Zhang W, Krasnikov BF, Heemskerk J, Young SS, Blass JP, Brown AM, Beal MF, Friedlander RM and Kristal BS (2004) Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology. J. Exp. Med. 200: 211–222
Schmitt E, Parcellier A, Ghiringhelli F, Casares N, Gurbuxani S, Droin N, Hamai A, Pequignot M, Hammann A, Moutet M, Fromentin A, Kroemer G, Solary E and Garrido C (2004) Increased immunogenicity of colon cancer cells by selective depletion of cytochrome. Cancer Res. 64: 2705–2711
Golstein P, Aubry L and Levraud JP (2003) Cell-death alternative model organisms: why and which? Nat. Rev. Mol. Cell Biol. 4: 798–807
Hannon GJ and Rossi JJ (2004) Unlocking the potential of the human genome with RNA interference. Nature 431: 371–378
Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B and Tschopp J (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1: 489–495
Schneider-Brachert W, Tchikov V, Neumeyer J, Jakob M, Winoto-Morbach S, Held-Feindt J, Heinrich M, Merkel O, Ehrenschwender M, Adam D, Mentlein R, Kabelitz D and Schutze S (2004) Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity 21: 415–428
Acknowledgements
We thank Philippe Dessen (IGR) and Jonathan Ewbank (CIML) for critical discussions. This work was supported by grants from Association pour la Recherche contre le Cancer, Ministère de la Recherche et de la Technologie, Ligue Nationale contre le Cancer and the European Commission (FP6, TransDeath LSHG-CT-2004-511983).
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Golstein, P., Kroemer, G. Redundant cell death mechanisms as relics and backups. Cell Death Differ 12 (Suppl 2), 1490–1496 (2005). https://doi.org/10.1038/sj.cdd.4401607
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DOI: https://doi.org/10.1038/sj.cdd.4401607
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