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

Abstract

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.