Autophagy in the cellular energetic balance

Abstract

Autophagy mediates the degradation of cellular components in lysosomes, assuring removal of altered or dysfunctional proteins and organelles. Autophagy is not only activated in response to cellular damage; in fact, one of its strongest and better-characterized stimuli is starvation. Activation of autophagy when nutrients are scarce allows cells to reutilize their own constituents for energy. Besides protein breakdown, autophagy also contributes to the mobilization of diverse cellular energy stores. This recently discovered interplay between autophagy and lipid and carbohydrate metabolism reveals the existence of a dynamic feedback between autophagy and cellular energy balance.

Figure 1. Molecular components of mammalian autophagic pathways

Scheme of three different types of autophagy co-existing in mammals. Macroautophagy: A limiting membrane forms de novo engulfing cytosolic components, and seals to form an autophagosome. Degradation occurs when autophagosomes fuse with lysosomes. Initiation of macroautophagy requires assembly and activation of the lipid kinase complex, class III PI3K that serves to recruit components of the two conjugation cascades, the LC3/PE and Atg5/12 cascades to the limiting membrane. Chaperone-mediated autophagy (CMA): When a cytosolic chaperone (hsc70) recognizes a targeting motif (KFERQ) in cytosolic proteins and delivers them to the lysosomal membrane. Upon binding to the lysosome-associated protein type 2A, substrate proteins unfold and cross the lysosomal membrane assisted by a lumenal chaperone. Microautophagy: Invaginations at the lysosomal membrane trap cytosolic cargo that is internalized after the vesicles pinch off into the lysosomal lumen. AA: amino acids; FA: free fatty acids; Atg: autophagy-related protein; PE: phosphatidylethanolamine.

Figure 2. Nutritional regulation of macroautophagy

Top: Under normal nutritional conditions mTOR 1) phosphorylates ULK1 which locks the ULK1-ATG13-FIP200 complex at the TORC1 complex and prevents its interaction with AMPK, and 2) inactivates DAP1 by phosphorylation. Bottom: During starvation, AMPK phosphorylates ULK1 favoring its release from TORC1 and its association to the site of isolation membrane formation. Reduced mTOR activity decreases DAP1 phosphorylation that through its inhibitory effect on macroautophagy prevents abnormal upregulation of this pathway. The positive feedback loops between AMPK, sestrins and p53 are shown. Independent of its transcriptional activity, cytosolic p53 can exert a direct inhibitory effect on macroautophagy.

Figure 3. Different catabolic pathways converge in lysosomes

Macroautophagy contributes to the delivery of proteins, lipid stores and glycogen for breakdown into lysosomes. The constituent components of these macromolecules exit the lysosome and become available for production of energy. In the case of protein breakdown, the resulting amino acids may have less energetic value and be preferentially utilized for the synthesis of new proteins. Levels of amino acids, free fatty acids and sugars circulating in blood or in the extracellular media have a direct impact on intracellular macroautophagy.

Figure 4. Autophagy in the metabolism of cellular lipid stores

A. Autophagy constitutively mobilizes cellular lipid droplets by macrolipophagy. Lipid droplets are sequestered inside autophagosomes and delivered to the lysosomes for degradation, resulting in free fatty acid release for cellular respiration. B. During acute lipid challenge most cells maximally activate macrolipophagy to prevent excessive cellular lipid accumulation. C. Chronically maintained lipid challenges reduce macroautophagic degradation of lipids by decreasing the efficiency of autophagosome-lysosomal fusion, leading to further cellular lipid accumulation.