Autophagy-dependent cell death

Abstract

Autophagy-dependent cell death can be defined as cell demise that has a strict requirement of autophagy. Although autophagy often accompanies cell death following many toxic insults, the requirement of autophagic machinery for cell death execution, as established through specific genetic or chemical inhibition of the process, is highly contextual. During animal development, perhaps the best validated model of autophagy-dependent cell death is the degradation of the larval midgut during larval-pupal metamorphosis, where a number of key autophagy genes are required for the removal of the tissues. Surprisingly though, even in the midgut, not all of the 'canonical' autophagic machinery appears to be required. In other organisms and cancer cells many variations of autophagy-dependent cell death are apparent, pointing to the lack of a unifying cell death pathway. It is thus possible that components of the autophagy machinery are selectively utilised or repurposed for this type of cell death. In this review, we discuss examples of cell death that utilise autophagy machinery (or part thereof), the current knowledge of the complexity of autophagy-dependent cellular demise and the potential mechanisms and regulatory pathways involved in such cell death.

Fig. 1

Roles of autophagy in cell death. The role of autophagy in cell death can be: autophagy-associated cell death, where the induction of autophagy accompanies apoptosis (or other cell death pathways); autophagy-mediated cell death, where the autophagy pathway activates apoptosis (or other cell death modalities); and autophagy-dependent cell death, which occurs independently of apoptosis or necrosis (e.g. Drosophila larval midgut degradation). An additional context-specific mode of cell death involves the coordinated action of both apoptosis and autophagy in parallel (e.g. Drosophila salivary gland degradation [70]), and Bax- and Bak-mediated induction of both apoptosis and autophagy [116]

Fig. 2

Degradation of the Drosophila larval midgut. During metamorphosis, an increase in the steroid hormone ecdysone triggers the degradation of the larval midgut by autophagy-dependent cell death. Stages of midgut removal observed by GFP in whole animals, from the onset of metamorphosis at 0 h relative to puparium formation (hRPF) during midgut degradation at 4 hRPF and following midgut condensation at 12 hRPF. The degradation is characterised by the initial contraction of the gastric caeca followed by condensation of the midgut body (scale bar represents 200 μm)

Fig. 3

Possible targets of autophagy during cell death. The cellular targets engulfed during autophagy-dependent cell death remain to be determined. Examples of possible targets include the bulk engulfment of cytoplasmic contents including cytosol and organelles or forms of selective autophagy that promote the clearance of mitochondria (e.g. mitophagy) or ubiquitinated proteins (e.g. aggrephagy)