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Autophagy at the crossroads of catabolism and anabolism

Key Points

  • Autophagy is a conserved catabolic process that degrades cytoplasmic constituents and organelles in the lysosome.

  • Autophagy was originally believed to non-selectively sequester and degrade cytoplasmic material. However, it is increasingly being appreciated that autophagy is a selective process, resulting in the targeted engulfment of specific cargoes such as mitochondria, peroxisomes and ribosomes, and protein aggregates.

  • Although protein catabolism is a salient feature of autophagy, recent research has uncovered that autophagy mobilizes diverse cellular energy and nutrient stores such as lipids, carbohydrates and iron.

  • In certain contexts, autophagic degradation is tightly linked with anabolic processes within cells. For example, autophagy-derived amino acids are important for enabling protein synthesis in mammalian cells.

  • During starvation, multiple transcriptional networks coordinate the autophagic degradation of intracellular lipids (lipophagy) in conjunction with other processes, promoting lipid catabolism.

  • Recent research demonstrating the selective autophagic degradation of iron–ferritin complexes has uncovered the importance of autophagy in mobilizing cellular nutrient stores.

Abstract

Autophagy is a conserved catabolic process that degrades cytoplasmic constituents and organelles in the lysosome. Starvation-induced protein degradation is a salient feature of autophagy but recent progress has illuminated how autophagy, during both starvation and nutrient-replete conditions, can mobilize diverse cellular energy and nutrient stores such as lipids, carbohydrates and iron. Processes such as lipophagy, glycophagy and ferritinophagy enable cells to salvage key metabolites to sustain and facilitate core anabolic functions. Here, we discuss the established and emerging roles of autophagy in fuelling biosynthetic capacity and in promoting metabolic and nutrient homeostasis.

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Figure 1: Overview of mammalian autophagy pathways.
Figure 2: Autophagy-derived metabolites support diverse anabolic functions.
Figure 3: Transcriptional control of lipophagy.
Figure 4: Ferritinophagy.

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Acknowledgements

The authors are grateful to T. Marsh for critically reading the manuscript. J.D. is supported by the US National Institutes of Health (CA126792 and CA188404), the Department of Defense Breast Cancer Research Program (W81XWH-11-1-0130) and the Samuel Waxman Cancer Research Foundation.

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Correspondence to Jayanta Debnath.

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PowerPoint slides

Glossary

Ubiquitin–proteasome system

(UPS). The cellular quality control pathway that tags and degrades unwanted or superfluous proteins.

Basal autophagy

A constitutive autophagic degradation process that proceeds in the absence of any overt stress or stimulus and serves important housekeeping roles.

Autophagosomes

Double membrane-bound vesicles that sequester cytoplasmic materials and target them for lysosomal degradation during macroautophagy.

Unfolded protein response

The activation of a stress response in the endoplasmic reticulum due to an increase in misfolded or aggregated proteins.

Autophagy-related proteins

(ATGs). Autophagy regulators.

Autophagy cargo receptors

Adaptor proteins that mediate the targeting of autophagosomes to cargo (for example, mitochondria and protein aggregates), often via ubiquitin and LC3-binding domains.

Methylotrophic yeasts

A genera of yeast that can only use methanol as the sole source of carbon and energy.

Midbody

An intercellular bridge connecting the two dividing cells at the end of cytokinesis that functions to localize the site of abscission.

Midbody ring

A densely ubiquitylated ring-like macromolecular assembly of several proteins located at the midbody during the telomeric phase of cytokinesis.

mTOR–autophagy special coupling compartment

(TASCC). A recently discovered membrane compartment that is adjacent to Golgi apparatus. The TASCC is highly enriched for both mTOR and autolysosomes and promotes the synthesis of secretory proteins.

Glomerular podocytes

Highly specialized epithelial cells in kidney that are terminally differentiated and serve as an important component of the glomerular filtration barrier.

Gluconeogenesis

A process of glucose production by the metabolism of non-carbohydrate substrates such as pyruvate, lactate, oxaloacetate, glucogenic amino acids or fatty acids.

β-oxidation

The breakdown of fatty acids in the mitochondria into two carbon units of acetyl-CoA, which enter the citric acid cycle, and NADH and FADH2.

Hepatic steatosis

The accumulation of fat in the liver.

Orexigenic

A stimulant (drug or hormone) that increases appetite.

Hyperphagia

An abnormal increase in appetite for the consumption of food, which is frequently associated with a defect in hypothalamic function.

Phosphorolytic degradation

The addition of a phosphate group to a substrate that initiates its cleavage.

Extensor digitorum longus muscle fibres

An example of a type II, fast-twitch muscle that has the ability to contract quickly and strongly but gets fatigued very rapidly.

Soleus muscles

An example of a type I, slow-twitch muscle that contains more mitochondria than type II, fast-twitch muscles; type I muscles contract for longer periods of time than type II muscles.

Pompe disease

Also called glycogen storage disease type II, Pompe disease is caused by a defect in lysosomal acid α-glucosidase.

Danon disease

A glycogen storage disease caused by a mutation in the gene encoding lysosome-associated membrane protein 2 (LAMP2).

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Kaur, J., Debnath, J. Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol 16, 461–472 (2015). https://doi.org/10.1038/nrm4024

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