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.