Abstract
Dying cells often display a large-scale accumulation of autophagosomes and hence adopt a morphology called autophagic cell death. In many cases, it is agreed that this autophagic cell death is cell death with autophagy rather than cell death by autophagy. Here, we evaluate the accumulating body of literature that argues that cell death occurs by autophagy. We also list the caveats that must be considered when deciding whether or not autophagy is an important effector mechanism of cell death.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kroemer, G. et al. Classifications of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 10 Oct 2008 (doi: 10.1038/cdd.2008.150).
Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).
Lockshin, R. A. & Zakeri, Z. Programmed cell death and apoptosis: origins of the theory. Nature Rev. Mol. Cell Biol. 2, 545–550 (2001).
Wyllie, A. H., Kerr, J. F. & Currie, A. R. Cell death: the significance of apoptosis. Int. Rev. Cytol. 68, 251–306 (1980).
Yuan, J. & Horvitz, H. R. A first insight into the molecular mechanisms of apoptosis. Cell 116, S53–S56 (2004).
Nicholson, D. W. et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376, 37–43 (1995).
Levine, B. & Klionsky, D. J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 6, 463–477 (2004).
Maiuri, C., Zalckvar, E., Kimchi, A. & Kroemer, G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature Rev. Mol. Cell Biol. 8, 741–752 (2007).
Tanaka, Y. et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406, 902–906 (2000).
Anglade, P. et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol. Histopathol. 12, 25–31 (1997).
Kitanaka, C. et al. Increased Ras expression and caspase-independent neuroblastoma cell death: possible mechanism of spontaneous neuroblastoma regression. J. Natl Cancer Inst. 94, 358–368 (2002).
Overmeyer, J. H., Kaul, A., Johnson, E. E. & Maltese, W. A. Active Ras triggers death in glioblastoma cells through hyperstimulation of macropinocytosis. Mol. Cancer Res. 6, 965–977 (2008).
Kanzawa, T. et al. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 11, 448–457 (2004).
Shao, Y., Gao, Z., Marks, P. A. & Jiang, X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc. Natl Acad. Sci. USA 101, 18030–18035 (2004).
Katayama, M., Kawaguchi, T., Berger, M. S. & Pieper, R. O. DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ. 14, 548–558 (2007).
Carew, J. S. et al. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr–Abl-mediated drug resistance. Blood 110, 313–322 (2007).
Yu, L. et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500–1502 (2004).
Shimizu, S. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biol. 6, 1221–1228 (2004).
Samara, C., Syntichaki, P. & Tavernarakis, N. Autophagy is required for necrotic cell death in Caenorhabditis elegans. Cell Death Differ. 15, 105–112 (2008).
Berry, D. L. & Baehrecke, E. H. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131, 1137–1148 (2007).
Koike, M. et al. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic–ischemic injury. Am. J. Pathol. 172, 454–469 (2008).
Shintani, T. & Klionsky, D. J. Autophagy in health and disease: a double-edged sword. Science 306, 990–995 (2004).
Codogno, P. & Meijer, A. J. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ. 12 (Suppl. 2), 1509–1518 (2005).
Baehrecke, E. H. Autophagy: dual roles in life and death? Nature Rev. Mol. Cell Biol. 6, 505–510 (2005).
Tsujimoto, Y. & Shimizu, S. Another way to die: autophagic programmed cell death. Cell Death Differ. 12 (Suppl. 2), 1528–1534 (2005).
Kroemer, G. & Jaattela, M. Lysosomes and autophagy in cell death control. Nature Rev. Cancer 5, 886–897 (2005).
Akar, U. et al. Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy 4, 669–679 (2008).
Turcotte, S. et al. A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14, 90–102 (2008).
Kim, K. W., Moretti, L. & Lu, B. M867, a novel selective inhibitor of caspase-3 enhances cell death and extends tumor growth delay in irradiated lung cancer models. PLoS ONE 3, e2275 (2008).
Rashmi, R., Pillai, S. G., Vijayalingam, S., Ryerse, J. & Chinnadurai, G. BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 27, 1366–1375 (2008).
Wang, M. et al. A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells. J. Biol. Chem. 283, 18678–18684 (2008).
Scarlatti, F., Maffei, R., Beau, I., Codogno, P. & Ghidoni, R. Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. Cell Death Differ. 15, 1318–1329 (2008).
Reef, S. et al. A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death. Mol. Cell 22, 463–475 (2006).
Xu, Z. X. et al. A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase. Cell Death Differ. 14, 1948–1957 (2007).
Chen, Y., McMillan-Ward, E., Kong, J., Israels, S. J. & Gibson, S. B. Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ. 15, 171–182 (2008).
Qu, X. et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128, 931–946 (2007).
Thorburn, A. Studying autophagy's relationship to cell death. Autophagy 4, 391–394 (2008).
Lindsten, T. et al. 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 (2000).
Zong, W. X., Lindsten, T., Ross, A. J., MacGregor, G. R. & Thompson, C. B. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev. 15, 1481–1486 (2001).
Wei, M. C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).
Tresse, E., Kosta, A., Luciani, M. F. & Golstein, P. From autophagic to necrotic cell death in Dictyostelium. Semin. Cancer Biol. 17, 94–100 (2007).
Kosta, A. et al. Autophagy gene disruption reveals a non-vacuolar cell death pathway in Dictyostelium. J. Biol. Chem. 279, 48404–48409 (2004).
Golstein, P. & Kroemer, G. Cell death by necrosis: towards a molecular definition. Trends Biochem. Sci. 32, 37–43 (2007).
Xue, L., Borutaite, V. & Tolkovsky, A. M. Inhibition of mitochondrial permeability transition and release of cytochrome c by anti-apoptotic nucleoside analogues. Biochem. Pharmacol. 64, 441–449 (2002).
Scarlatti, F., Granata, R., Meijer, A. J. & Codogno, P. Does autophagy have a license to kill mammalian cells? Cell Death Differ. 4 July 2008 (doi: 10.1038/cdd.2008.101).
Chatterjee, T., Muhkopadhyay, A., Khan, K. A. & Giri, A. K. Comparative mutagenic and genotoxic effects of three antimalarial drugs, chloroquine, primaquine and amodiaquine. Mutagenesis 13, 619–624 (1998).
McManus, M. T. & Sharp, P. A. Gene silencing in mammals by small interfering RNAs. Nature Rev. Genet. 3, 737–747 (2002).
Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
Matsumoto, N. et al. Comprehensive proteomics analysis of autophagy-deficient mouse liver. Biochem. Biophys. Res. Commun. 368, 643–649 (2008).
Cao, Y. & Klionsky, D. J. Physiological functions of Atg6/Beclin 1: a unique autophagy-related protein. Cell Res. 17, 839–849 (2007).
Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).
Yousefi, S. et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nature Cell Biol. 8, 1124–1132 (2006).
Levine, B. & Yuan, J. Autophagy in cell death: an innocent convict? J. Clin. Invest. 115, 2679–2688 (2005).
Berry, D. L. & Baehrecke, E. H. Autophagy functions in programmed cell death. Autophagy 4, 359–360 (2008).
Akdemir, F. et al. Autophagy occurs upstream or parallel to the apoptososome during histolytic cell death. Development 133, 1457–1465 (2006).
Espert, L. et al. Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J. Clin. Invest. 116, 2161–2172 (2006).
Kunchithapautham, K. & Rohrer, B. Apoptosis and autophagy in photoreceptors exposed to oxidative stress. Autophagy 3, 433–441 (2007).
Ding, W. X. et al. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J. Biol. Chem. 282, 4702–4710 (2006).
Crighton, D. et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121–134 (2006).
Yu, L. et al. Autophagic programmed cell death by selective catalase degradation. Proc. Natl Acad. Sci. USA 103, 4952–4957 (2006).
Scott, R. C., Juhasz, G. & Neufeld, T. P. Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death. Curr. Biol. 17, 1–11 (2007).
Zhu, C. et al. Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia–ischemia. Cell Death Differ. 14, 775–784 (2007).
Gidday, J. M. Cerebral preconditioning and ischaemic tolerance. Nature Rev. Neurosci. 7, 437–448 (2006).
Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).
Galluzzi, L. et al. Cell death modalities: classification and pathophysiological implications. Cell Death Differ. 14, 1237–1243 (2007).
Kroemer, G. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ. 12 (Suppl. 2), 1463–1467 (2005).
Festjens, N., Vanden Berghe, T. & Vandenabeele, P. Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim. Biophys. Acta 1757, 1371–1387 (2006).
Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nature Chem. Biol. 4, 313–321 (2008).
Ogura, K. et al. Caenorhabditis elegans unc-51 gene required for axonal elongation encodes a novel serine/threonine kinase. Genes Dev. 8, 2389–2400 (1994).
Zhou, X. et al. Unc-51-like kinase 1/2-mediated endocytic processes regulate filopodia extension and branching of sensory neurons. Proc. Natl Acad. Sci. USA 104, 5842–5847 (2007).
Jounai, N. et al. The Atg5–Atg12 conjugate associates with innate antiviral immune responses. Proc. Natl Acad. Sci. USA 104, 14050–14055 (2007).
Kametaka, S., Okano, T., Ohsumi, M. & Ohsumi, Y. Apg14p and Apg6/Vps30p form a protein complex essential for autophagy in the yeast, Saccharomyces cerevisiae. J. Biol. Chem. 273, 22284–22291 (1998).
Takahasi, Y. et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nature Cell Biol. 9, 1142–1151 (2007).
Takahashi, Y. et al. Loss of Bif-1 suppresses Bax/Bak conformational change and mitochondrial apoptosis. Mol. Cell. Biol. 25, 9369–9382 (2005).
Perelman, B. et al. Molecular cloning of a novel human gene encoding a 63-kDa protein and its sublocalization within the 11q13 locus. Genomics 41, 397–405 (1997).
Iida, A. et al. Identification of a gene disrupted by inv(11)(q13.5;q25) in a patient with left–right axis malformation. Hum. Genet. 106, 277–287 (2000).
Maiuri, C. et al. Functional and physical interaction between Bcl-XL and the BH3 domain of Beclin-1. EMBO J. (in the press).
Fimia, G. M. et al. Ambra1 regulates autophagy and development of the nervous system. Nature 447, 1121–1125 (2007).
Massey, D. & Parkes, M. Genome-wide association scanning highlights two autophagy genes, ATG16L1 and IRGM, as being significantly associated with Crohn's disease. Autophagy 3, 649–651 (2007).
Bolanos-Meade, J. et al. Hydroxychloroquine causes severe vacuolar myopathy in a patient with chronic graft-versus-host disease. Am. J. Hematol. 78, 306–309 (2005).
Nishino, I. Autophagic vacuolar myopathy. Semin. Pediatr. Neurol. 13, 90–95 (2006).
Acknowledgements
The authors are supported by grants to B.L. from the National Institutes of Health, American Cancer Society and Ellison Medical Foundation, and to G.K. from Ligue Nationale Contre le Cancer (Equipe labellisée), Agence Nationale de Recherche, Institut National du Cancer, Cancéropôle Île-de-France, the European Union (ApoSys, ChemoRes, DeathTrain, RIGHT) and the Fondation pour la Recherche Médicale.
Author information
Authors and Affiliations
Corresponding author
Related links
Related links
DATABASES
OMIM
FURTHER INFORMATION
Rights and permissions
About this article
Cite this article
Kroemer, G., Levine, B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 9, 1004–1010 (2008). https://doi.org/10.1038/nrm2529
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrm2529
This article is cited by
-
Icariin exerts anti-tumor activity by inducing autophagy via AMPK/mTOR/ULK1 pathway in triple-negative breast cancer
Cancer Cell International (2024)
-
Multipronged regulation of autophagy and apoptosis: emerging role of TRIM proteins
Cellular & Molecular Biology Letters (2024)
-
Friend or foe: role of pathological tau in neuronal death
Molecular Psychiatry (2023)
-
Discovery of rafoxanide as a novel agent for the treatment of non-small cell lung cancer
Scientific Reports (2023)
-
Radiation induces IRAK1 expression to promote radioresistance by suppressing autophagic cell death via decreasing the ubiquitination of PRDX1 in glioma cells
Cell Death & Disease (2023)