All cells have internal nutrient stores for use during starvation. Glycogen and lipid droplets are overtly designed for this purpose. Their contents are accessed primarily through the actions of dedicated enzymes, such as glycogen phosphorylase and hormone-sensitive lipase. Many other cellular components have a dual function as nutrient stores. For example, ribosomes occupy ~50% of the dry weight of rapidly growing microbes. In addition to enabling rapid protein synthesis when nutrient conditions are favorable, this provides a store of amino acids for proteome remodeling when conditions turn for the worse. Autophagy has a key role in providing access to such undedicated nutrient stores.
Limitation for any of the major elemental nutrients triggers autophagy in yeast, with nitrogen limitation the strongest stimulus (14
). When nitrogen is removed, yeast defective in autophagy become severely depleted of internal amino acids. This precludes the synthesis of proteins important for surviving nitrogen starvation and accelerates cell death (15
). Thus, autophagy provides the primary route to nitrogen during starvation.
Unlike microbes, mammalian cells benefit from a relatively constant nutrient environment. Nevertheless, autophagy can support mammalian cells through nutrient deprivation. For example, in lymphocytes, the ability to consume environmental nutrients is growth factor–dependent. In the absence of growth factor stimulation, energy charge is maintained through autophagy, with cells shrinking ~50% in size over 3 months of self-cannibalization (16
At the organismal level, autophagy is required at multiple stages of mammalian development. The first directly follows oocyte fertilization, with autophagy essential to feed the developing embryo before it gains access to the maternal blood supply. Autophagy-defective embryos fail to reach the blastocyst stage (17
). Maternally supplied autophagy proteins enable autophagy-deficient offspring to complete embryogenesis, revealing a second requirement for autophagy: when access to the maternal blood supply is suddenly lost due to birth. Autophagy-defective pups die within 24 hours of delivery. Both circulating and tissue amino acid levels are reduced, and AMPK is activated in the heart, which shows electrocardiographic changes analogous to those observed with severe myocardial infarction (18
In adult starvation, autophagy also has a central role, increasing within 24 hours in liver, pancreas, kidney, skeletal muscle, and heart; the brain is spared (19
). Pharmacological blockade of autophagy results in cardiac dysfunction early in starvation (20
). Although autophagy levels return to normal in liver 2 days into starvation, it remains increased in both cardiac and skeletal muscle. Liver mass, however, persistently falls faster than muscle or total body mass. This decline is consistent with a failure of biosynthesis to balance basal consumption of liver by autophagy (21
). As liver mass falls, breakdown of muscle and adipose tissue feeds the liver, which exports glucose and ketone bodies required by the brain ().
Fig. 3 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 (more ...)