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  • Review Article
  • Published:

Self-eating and self-killing: crosstalk between autophagy and apoptosis

Nature Reviews Molecular Cell Biology volume 8, pages 741–752 (2007)Cite this article

Key Points

  • Apoptosis and autophagy constitute the two self-destructive processes by which supernumerary, damaged or aged cells and organelles are eliminated. Beyond this homeostatic function, autophagy is also a process through which cells adapt their metabolisms to starvation, imposed by decreased extracellular nutrients or by decreased intracellular metabolite concentrations that result from growth-factor signalling.

  • The relationship between autophagy and cell death is complex because autophagy constitutes an adaptive response to different kinds of stress by which the cells avoid cell death; yet, in some settings, it can also contribute to the demise of cells.

  • In response to the same panoply of stressors, cells can preferentially undergo apoptosis or autophagy, a choice that is dictated by the intensity of the stimulus and thresholds for either response. Several stress mediators (reactive oxygen species, ceramide, elevation of cytosolic Ca2+), isoforms of p19ARF (or its human homologue, p14ARF), p53, BH3-only proteins and death-associated protein kinases (DAPK family members) can stimulate both apoptosis and autophagy.

  • Organellar stress that affects mitochondria and the endoplasmic reticulum can induce a specific autophagic response that leads to the removal of damaged organelles (mitophagy and reticulophagy, respectively) and protects cells. Beyond a threshold (which is lowered when autophagy is inhibited), such stress causes apoptosis.

  • Several proteins that have an essential role in autophagy have a direct or indirect impact on the regulation or execution of apoptosis. As an example, Atg5 is an essential autophagy inducer, yet it can be cleaved by calpain cysteine proteases to lose its pro-autophagy effects and become a pro-apoptotic molecule.

  • Beclin-1 (or its yeast homologue Atg6) interacts with the anti-apoptotic multidomain proteins of the BCL2 family (in particular BCL2 and BCL-XL) through a BH3 domain. BH3-only proteins and pharmacological BH3 mimetics competitively disrupt the inhibitory interaction between beclin-1 and BCL2 or BCL-XL, thereby stimulating autophagy. Thus, BH3 domains, which are well known for their apoptosis-inducing property, can also stimulate autophagy.

  • The pharmacological stimulation of autophagy may have cytoprotective effects, for example, in mouse models of neurodegenerative disease, whereas the inhibition of autophagy can sensitize cancer cells to chemotherapy to promote p53-induced apoptosis. Thus, manipulation of autophagy can determine cell-fate decisions in clinical settings.

Abstract

The functional relationship between apoptosis ('self-killing') and autophagy ('self-eating') is complex in the sense that, under certain circumstances, autophagy constitutes a stress adaptation that avoids cell death (and suppresses apoptosis), whereas in other cellular settings, it constitutes an alternative cell-death pathway. Autophagy and apoptosis may be triggered by common upstream signals, and sometimes this results in combined autophagy and apoptosis; in other instances, the cell switches between the two responses in a mutually exclusive manner. On a molecular level, this means that the apoptotic and autophagic response machineries share common pathways that either link or polarize the cellular responses.

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Figure 1: The relationship between apoptosis and autophagy.
Figure 2: Regulation of autophagy and apoptosis by p53 and p19ARF/p14ARF.
Figure 3: BH3 proteins and mimetics act on the beclin-1–BCL2 interaction.
Figure 4: Molecular switches between apoptosis and autophagy.
Figure 5: Scenarios for the interaction between apoptosis and autophagy.

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Acknowledgements

The authors are supported by grants from the Ligue Nationale contre le Cancer (équipe labellisée), the European Union (Death-Train, ChemoRes, Trans-Death, Right, active p53), Cancéropôle Ile-de-France, Institut National du Cancer, Agence Nationale pour la Recherche (to G.K.) and the Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI) (to A.K.). A.K. is the incumbent Helena Rubinstein Chair of Cancer Research.

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Authors and Affiliations

  1. INSERM, U848, Villejuif, F-94805, France

    M. Chiara Maiuri & Guido Kroemer

  2. Institut Gustave Roussy, Villejuif, F-94805, France

    M. Chiara Maiuri & Guido Kroemer

  3. Dipartimento di Farmacologia Sperimentale, Università degli Studi di Napoli Federico II, Facoltà di Scienze Biotecnologiche, 80131, Napoli, Italy

    M. Chiara Maiuri

  4. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel

    Einat Zalckvar & Adi Kimchi

  5. Université Paris-Sud, Villejuif, F-94805, France

    Guido Kroemer

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Examples of cell death exacerbated by inhibition of autophagy (PDF 159 kb)

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DATABASES

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Parkinson's disease

Peutz–Jeghers syndrome

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Glossary

Autophagy

In this context, autophagy is used synonymously with macroautophagy, a process in which a portion of the cytoplasm is engulfed by a specific membrane and later digested by lysosomal enzymes.

Programmed cell death

A genetically controlled cell-death process that is turned on in response to external or internal signals.

Lysosome

A membrane-surrounded sac that contains >50 acid hydrolases (phosphatases, nucleases, glycosidases, proteases, peptidases, sulphatases and lipases), which can digest all of the major macromolecules of the cell to breakdown products that are then available for metabolic reuse.

Catabolism

A metabolic state that leads to the degradation of macromolecules to yield small molecules and/or ATP, usually as a consequence of nutrient deprivation. Catabolic reactions include glycogenolysis, β-oxidation of fatty acids and autophagy.

BCL2 family

A family of proteins that contain at least one BCL2 homology (BH) region. The family is divided into anti-apoptotic multidomain proteins (such as BCL2, BCL-XL and MCL1), which contain four BH domains (BH1, BH2, BH3, BH4), pro-apoptotic multidomain proteins (for example, BAX and BAK), which contain BH1, BH2 and BH3, and the pro-apoptotic BH3-only protein family.

Mitochondrial outer membrane permeabilization

(MOMP). An apoptosis-associated process that results in apoptosis-inducing proteins (such as cytochrome c, apoptosis-inducing factor, Smac/Diablo) that are normally retained in the mitochondrial intermembrane space being released through the outer membrane into the cytosol.

Autolysosome

Also called autophagolysosome. A vesicle that is formed by the fusion of an autophagosome (or an amphisome) with a lysosome.

Caspase

One of a family of cysteine proteases that cleave after aspartate residues in substrate proteins. Initiator caspases are typically activated in response to a specific triggering event (for example, caspase-8 upon death-receptor ligation, caspase-9 upon apoptosome activation, caspase-2 upon DNA damage), whereas effector caspases (mainly caspase-3, -6 and -7) are important for the ordered dismantling of vital cellular structures.

Reactive oxygen species

(ROS). Reduced derivatives of molecular oxygen (O2), including classical oxygen radicals and peroxides, which are formed within cells.

Death receptor

One of a family of cell-surface receptors that mediate cell death upon ligand-induced trimerization. The best-studied members include tumour necrosis factor receptor-1 (TNFR1), FAS (or CD95, which binds FAS ligand) and two receptors for TNF-related apoptosis-inducing ligand (TRAILR1 and -R2).

Cytochrome c

A haem protein that is normally confined to the mitochondrial intermembrane space. Upon induction of apoptosis, cytochrome c is released from mitochondria and triggers the formation of the apoptosome, a caspase activation complex.

Apoptosome

A complex that forms when cytochrome c is released from mitochondria and interacts with the cytosolic protein APAF1, which, in turn, recruits pro-caspase-9. In the presence of ATP, this interaction results in the allosteric activation of caspase-9 and in the subsequent activation of the effector caspase-3.

Apoptosis-inducing factor

(AIF). A flavoprotein that is normally present in the mitochondrial intermembrane space. Following apoptosis induction, AIF translocates to the nucleus where it activates a molecular complex that causes large-scale DNA fragmentation, presumably in a caspase-independent fashion.

Lysosomal membrane permeabilization

(LMP). A perturbation of lysosomal membrane function, leading to the translocation of lysosomal hydrolases (including cathepsins) from the lysosomal lumen to the rest of the cell. LMP can be induced by endogenous signal transducers (such as reactive oxygen species and sphingosine) as well as by lysosomotropic drugs.

Cathepsin

A protease that localizes mainly to lysosomes and lysosome-like organelles. Cathepsin proteases can be divided into three subgroups according to their active-site amino acid: cysteine (cathepsins B, C, H, F, K, L, O, S, V, W and X/Z), aspartate (cathepsins D and E) and serine (cathepsin G).

Haploinsufficient

A gene that requires biallelic expression to produce the amount of protein that is sufficient to guarantee a normal biological function.

Tumour-suppressor gene

A gene that, when eliminated or inactivated, is permissive for the development of cancers. These genes often determine cell-cycle checkpoints or facilitate the induction of programmed cell death.

p53

A transcription factor that is activated by numerous genotoxic insults to induce cell-cycle arrest, cellular senescence or apoptosis. p53 is frequently mutated or functionally inactivated in cancer.

Oncogene

A gene of which overexpression or gain-of-function mutation contributes to oncogenesis.

Unfolded protein response

(UPR). A signalling pathway that is activated in response to stress in the endoplasmic reticulum (ER). The UPR can cope effectively with stress by reducing the amount of misfolded protein overload in the ER.

Heterophagy

Phagocytosis of a cell by another cell. Heterophagy has an important role in the efficient removal of apoptotic corpses. Efficient heterophagy is indispensable for avoiding inflammatory responses that are triggered by apoptotic material.

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Maiuri, M., Zalckvar, E., Kimchi, A. et al. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8, 741–752 (2007). https://doi.org/10.1038/nrm2239

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