Signaling pathways that regulate autophagy. Common nutrient, growth factor, hormone, and stress signals that regulate autophagy. Purple lines depict events that positively regulate autophagy. Yellow lines depict those that negatively regulate autophagy. Many pathways converge on the AMPK-mTORC1 axis. Green lines depict pathways that are mTOR-independent. Note that all input signals are framed as autophagy activators; thus, they include limitation for growth factors and nutrients. IKKβ, inhibitor of nuclear factor κB kinase β; PI3K, phosphatidylinositol-3 kinase; PTEN, phosphatase and tensin homolog; MAPK, mitogen-activated protein kinase; TSC1/2, tuberosclerosis complexes 1 and 2; and EF, elongation factor.

Role of autophagy in adult mammalian starvation. Depicted pathways predominate after depletion of glycogen stores, typically ~12 hours into starvation. Autophagy in liver and heart (but not brain) generates fatty acids and amino acids, which are catabolized to yield energy. In the liver, this energy drives gluconeogenesis and ketogenesis. Amino acids are substrates for both ketogenesis and gluconeogenesis; acetyl-CoA from fatty acids is only for ketogenesis. As starvation continues, degradation of adipose and muscle play an increasing role in supplying substrates to the liver, which exports glucose and ketone bodies to feed the brain. The relative importance of ketone bodies increases in prolonged starvation. NADH, reduced form of nicotinamide adenine dinucleotide.

Use of the products of autophagy. Multiple forms of stress activate autophagy (bottom right). Degradation of proteins, lipids, carbohydrates, and nucleic acids liberates amino acids, fatty acids, sugars, and nucleosides that are released into the cytoplasm for reutilization. Sugars (blue lines), including glucose released from glycogen granules by glycogenolysis or autophagy, are catabolized by glycolysis and the PPP to generate ATP, and pyruvate for subsequent TCA cycle metabolism. Nucleosides (green lines) are used for new nucleic acid synthesis and catabolized by the combined action of the PPP and glycolysis. Amino acids (purple lines) are used as building blocks for new protein synthesis, for ATP production by central carbon metabolism, and (in liver) as substrates for gluconeogenesis (Fig. 3). They also can be combined to yield citrate, which drives lipid synthesis and membrane biogenesis. Catabolism of amino acids yields ammonia, an activator of autophagy (dotted line). Fatty acids (yellow lines) from lipolysis or from autophagy of membranes or lipid droplets yield acetyl-CoA, which feeds the TCA cycle, supporting ATP production and citrate generation. OAA indicates oxaloacetate; α-KG, α-ketoglutarate; and ER, endoplasmic reticulum.