Autophagy as a decisive process for cell death

Abstract

Autophagy is an intracellular catabolic pathway in which cellular constituents are engulfed by autophagosomes and degraded upon autophagosome fusion with lysosomes. Autophagy serves as a major cytoprotective process by maintaining cellular homeostasis and recycling cytoplasmic contents. However, emerging evidence suggests that autophagy is a primary mechanism of cell death (autophagic cell death, ACD) and implicates ACD in several aspects of mammalian physiology, including tumor suppression and psychological disorders. However, little is known about the physiological roles and molecular mechanisms of ACD. In this review, we document examples of ACD and discuss recent progress in our understanding of its molecular mechanisms.

Fig. 1. Representative cases of autophagic cell death (ACD).

a The midgut of Drosophila larvae and pupae shows high caspase activity and autophagy flux, but midgut cell death depends only on autophagy. b Adult hippocampal neural stem cells (NSCs) undergo ACD following insulin withdrawal without the involvement of apoptosis or necroptosis. c During replicative crisis, DNA with telomeric damage is released into the cytosol and is recognized by cGAS and STRING, which induces ACD. d Cerebral ischemia–reperfusion induces mitophagy in a DRP1-dependent manner with subsequent neuronal cell death. e Chronic restraint stress (CRS) or corticosterone treatment induces ACD in adult hippocampal NSCs via SGK3 in vivo and in vitro. CRS decreases adult hippocampal neurogenesis, which is accompanied by anxiety, depression, and cognitive deficits.

Fig. 2. Molecular effectors in ACD of adult hippocampal NSCs following insulin withdrawal or psychological stress.

Insulin withdrawal activates GSK3B and AMPK, followed by AMPK-mediated phosphorylation of p62. RYR3 mediates the efflux of Ca²⁺ from the ER. PARKIN levels are upregulated in a GSK3B-dependent manner, and PARKIN is involved in the transfer of ER Ca²⁺ to mitochondria and depolarization of mitochondrial membrane potential. Both p62 and PARKIN promote mitophagy, leading to ACD. Cell death triggered by insulin withdrawal is switched from ACD to apoptosis by calpain 2 and VCP. High levels of corticosterone (CORT) induced by CRS cause ACD via SGK3, which has a PX domain for binding to PI3P and the initiation of autophagy. The dashed lines indicate that the process is not yet experimentally confirmed.