Emerging regulation and functions of autophagy

Abstract

Autophagy maintains cell, tissue and organism homeostasis through degradation. Complex post-translational modulation of the Atg (autophagy-related) proteins adds additional entry points for crosstalk with other cellular processes and helps define cell-type-specific regulations of autophagy. Beyond the simplistic view of a process exclusively dedicated to the turnover of cellular components, recent data have uncovered unexpected functions for autophagy and the autophagy-related genes, such as regulation of metabolism, membrane transport and modulation of host defenses--indicating the novel frontiers lying ahead.

Figure 1. The different types of autophagy.

(a) Macroautophagy is characterized by the sequestration of structures targeted for destruction into double-membrane vesicles called autophagosomes. Complete autophagosomes first fuse with endosomes before finally exposing their content to the hydrolytic interior of lysosomes. The resulting metabolites are transported into the cytoplasm and used either for the synthesis of new macromolecules or as a source of energy. (b) During chaperone-mediated autophagy, proteins carrying the pentapeptide KFERQ-like sequence are recognized by the Hsc70 chaperone, which then associates with the integral lysosome membrane protein LAMP-2A, triggering its oligomerization. This event leads the translocation of the bound protein into the lysosome interior through a process that requires Hsc70. (c) Microautophagy entails the recruitment of targeted components in proximity with the lysosomal membrane, which subsequently invaginates and pinches off.

Figure 2. Relationship between autophagy and the main metabolic pathways.

(a) The catabolic products of the intracellular structures that are targeted by autophagosomes, such as amino acids, lipids and sugars, are used for anabolic reactions to generate new proteins, glycans, oligonucleotides and membranes to sustain cell functions. Amino acids can also be used to maintain their systemic levels and for de novo synthesis of glycogen (gluconeogenesis) in the liver. Lipids and amino acids can enter the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to generate energy in the form of ATP. Sugars can also be metabolized to generate ATP through glycolysis and to maintain systemic glucose levels. (b,c) Metabolic compartmentalization between different cell types. (b) Inside tumours, hypoxia and oxidative stress trigger autophagy and mitophagy in the stromal fibroblasts. This induces a metabolic switch towards aerobic glycolysis (known as the Warburg effect), leading to the production of lactate and other metabolites that are liberated into the intracellular space and reabsorbed by tumour cells. A more oxidative metabolism in these cells generates oxidative stress and ammonia (from glutaminolysis), which signals back to fibroblasts to further stimulate autophagy. (c) In brain tissue, astrocytes produce lactate from glucose through glycolysis and glutamine through autophagy. These metabolites are taken up by neurons and oxidized to generate ATP. Moreover, the neurotransmitter glutamate, released by neurons, can be retransformed into glutamine by astrocytes.