Autophagy in cell death: an innocent convict?

Abstract

The visualization of autophagosomes in dying cells has led to the belief that autophagy is a nonapoptotic form of programmed cell death. This concept has now been evaluated using cells and organisms deficient in autophagy genes. Most evidence indicates that, at least in cells with intact apoptotic machinery, autophagy is primarily a pro-survival rather than a pro-death mechanism. This review summarizes the evidence linking autophagy to cell survival and cell death, the complex interplay between autophagy and apoptosis pathways, and the role of autophagy-dependent survival and death pathways in clinical diseases.Cell biologists have long recognized the possibility that eukaryotic cells may undergo nonapoptotic forms of programmed cell death. Autophagy, a lysosomal pathway involving the bulk degradation of cytoplasmic contents, has been identified as a prime suspect in such death, and recent studies have implicated the autophagy pathway as a cause of nonapoptotic cellular demise. However, most evidence linking autophagy to cell death is circumstantial. Now, with new tools to assess causality, it is an opportune time to revisit the case of autophagy in cell death. Is autophagy an innocent bystander, a direct death execution pathway, a defense mechanism that ultimately fails in its mission to preserve cell viability, and/or a garbage disposal mechanism that cleans up remnants of a cell already committed to die? Autophagy is a regulated lysosomal degradation pathwayThe term autophagy (Greek, "to eat oneself") does not refer to a death process; it denotes the process of self-cannibalization through a lysosomal degradation pathway. Autophagy is the cell's major regulated mechanism for degrading long-lived proteins and the only known pathway for degrading organelles (reviewed in refs. 1, 2). During autophagy, an isolation membrane forms, presumably arising from a vesicular compartment known as the preautophagosomal structure, invaginates, and sequesters cytoplasmic constituents including mitochondria, endoplasmic reticulum, and ribosomes (Figure 1). The edges of the membrane fuse to form a double or multimembranous structure, known as the autophagosome or autophagic vacuole. The outer membrane of the autophagosome fuses with the lysosome (in mammalian cells) or vacuole (in yeast and plants) to deliver the inner membranous vesicle to the lumen of the degradative compartment. Degradation of the sequestered material generates nucleotides, amino acids, and free fatty acids that are recycled for macromolecular synthesis and ATP generation.Autophagy occurs at low basal levels in all cells to perform homeostatic functions (e.g., cytoplasmic and organelle turnover) but is rapidly upregulated when cells need to generate intracellular nutrients and energy (e.g., during starvation or trophic factor withdrawal), undergo architectural remodeling (e.g., during developmental transitions), or rid themselves of damaging cytoplasmic components (e.g., during oxidative stress, infection, and accumulation of protein aggregates). Nutritional...

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