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.

Figure 1

The autophagy pathway and its role in cellular adaptation to nutrient deprivation. Starvation or growth factor deprivation results in a decrease in intracellular nutrients and activation of nutrient-sensing signaling pathways (reviewed in ref. 97) that stimulate autophagy. Autophagy involves the sequestration of cytoplasmic material by an isolation membrane (derived from the preautophagosomal structure) to form a double-membrane vacuole, the autophagosome. The autophagosome undergoes fusion with a late endosome or lysosome, to form an autolysosome, in which the sequestered material is degraded. Degradation of membrane lipids and proteins by the autolysosome generates free fatty acids and amino acids that can be reused by the cell to maintain mitochondrial ATP energy production and protein synthesis and thereby promote cell survival. Disruption of this pathway by autophagy gene inactivation prevents cell survival in diverse organisms (Table 2). The same molecular machinery and overlapping dynamic membrane rearrangement events that occur during starvation may also be used in other settings to degrade unwanted cytoplasmic contents, including damaged mitochondria, protein aggregates, and intracellular pathogens. See text for discussion. TCA cycle, tricarboxylic acid cycle.

Figure 2

The molecular mechanisms of autophagy. The autophagy (Atg) proteins can be divided into 4 functional groups, including (A) a protein kinase autophagy regulatory complex that responds to upstream signals, including nutrient limitation; (B) a lipid kinase signaling complex that mediates vesicle nucleation; (C) ubiquitin-like protein conjugation pathways that are required for vesicle expansion and completion; and (D) a retrieval pathway required for the disassembly of Atg protein complexes from matured autophagosomes. Shown are the yeast Atg proteins that participate in each functional group. Yeast Atg proteins with known orthologs in higher eukaryotes are underlined. PI, phosphatidylinositol; PI3-P, phosphatidylinositol 3-phosphate; PE, phosphatidylethanolamine.

Figure 3

Ultrastructural examples of apoptotic and autophagic cell death. Electron micrographs of a FasL-treated Jurkat cell undergoing cell death with apoptotic features (A) and of a tamoxifen-treated MCF7 human breast carcinoma cell undergoing cell death with autophagic features (B). In A, note chromatin condensation (cell in center) and cytoplasmic vacuolization (cell in upper right). In B, note absence of chromatin condensation and presence of numerous autophagosomes. Images in A and B reproduced with permission from Nature Cell Biology (98) and Landes Bioscience (90), respectively.