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Autophagy in metazoans: cell survival in the land of plenty

Key Points

  • Autophagy is a universally conserved response to nutrient limitation in which organisms respond to metabolic 'emergencies' by breaking down cytoplasmic proteins and organelles. The existence of autophagy in diverse organisms has been recognized for decades, but the functions of autophagy in mammals are still not fully understood.

  • In metazoans, metabolite supply is controlled by growth factor regulation of nutrient uptake, and decreased growth factor signalling permits the induction of autophagy. In various metazoan organisms, autophagy supports cell survival in such circumstances.

  • At the molecular level, the induction of autophagy seems to be linked to well-known mechanisms of intracellular nutrient sensing. In particular, the serine/threonine kinase mTOR promotes cap-dependent protein translation, and is therefore vital for the anabolic effects of growth factor signal transduction. By contrast, the inhibition of mTOR activity is associated with the induction of autophagy.

  • The benefits that autophagy provides to metazoan cells might include metabolite recycling for adaptive synthetic reactions or ATP production, and degradation of damaged or unnecessary material. In addition, autophagy is now recognized as a form of innate immunity against various intracellular pathogens.

  • Dysregulation of autophagy has been implicated in various pathological conditions, including tumorigenesis and neurodegeneration. In some circumstances, autophagy functions as a non-apoptotic form of cell death. The complexity of these responses is an active area of research and underlines the importance of autophagy in mammalian physiology.

Abstract

Cells require a constant supply of macromolecular precursors and oxidizable substrates to maintain viability. Unicellular eukaryotes lack the ability to regulate nutrient concentrations in their extracellular environment. So when environmental nutrients are depleted, these organisms catabolize existing cytoplasmic components to support ATP production to maintain survival, a process known as autophagy. By contrast, the environment of metazoans normally contains abundant extracellular nutrients, but a cell's ability to take up these nutrients is controlled by growth factor signal transduction. Despite evolving the ability to maintain a constant supply of extracellular nutrients, metazoans have retained a complete set of autophagy genes. The physiological relevance of autophagy in such species is just beginning to be explored.

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Figure 1: Growth factor signalling regulates autophagy.
Figure 2: A model for growth factor control of intermediate metabolism and autophagy.
Figure 3: Coordinated regulation of nutrient sensing by mTOR and AMPK.
Figure 4: Model for the metabolic benefits of autophagy.

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Acknowledgements

The authors wish to thank Daniel E. Bauer for insightful comments and suggestions during the preparation of this review. Julian J. Lum is supported by a fellowship from the Leukemia and Lymphoma Society. Ralph J. DeBerardinis is supported by a grant from the National Institutes of Health. Grants for the Thompson laboratory are provided in part by the National Institutes of Health.

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Correspondence to Craig B. Thompson.

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DATABASES

Entrez Gene

ATG1

ATG5

ATG6

ATG7

ATG8

ATG10

daf-2

PTEN

Swiss-Prot

Bak

Bax

CPT1

4E-BP1

Pex14

Rheb

S6K

TSC1

TSC2

Uth1

Glossary

OXIDIZABLE SUBSTRATE

A molecule that can be used in mitochondrial oxidation/reduction reactions to yield reduced electron carriers (NADH, FADH2). In this review, we consider oxidizable substrates to be molecules that provide carbon to the tricarboxylic acid cycle.

EXTRACELLULAR NUTRIENT

A resource in the environment that can be passively or actively taken up by cells and used in intermediate metabolism. These include amino acids, fatty acids, glucose, nucleotides and minerals.

GROWTH FACTOR

A small molecule that binds to lineage-specific cell-surface receptors and activates signal transduction pathways necessary for cell growth, proliferation and survival. Examples of growth factors include insulin, platelet-derived growth factor and cytokines.

ANABOLIC METABOLISM

(anabolism). A collective term for metabolic pathways in which simple metabolites are used to synthesize macromolecules. Examples include the synthesis of proteins from amino acids and of lipids from acetyl CoA. Anabolism is required for cell growth, is stimulated by growth factors and generally consumes ATP.

CATABOLIC METABOLISM

(catabolism). A collective term for metabolic pathways that degrade macromolecules to yield simpler constituents and/or ATP, usually during periods of nutrient deprivation. Examples include β-oxidation of fatty acids and glycogenolysis. Autophagy is considered as an arm of catabolism, because it includes protein degradation in response to nutritional stress.

MACROAUTOPHAGY

(autophagy). A process whereby double-membrane structures sequester cytosolic material and fuse to a lysosome or vacuole. Material within these structures is degraded and recycled.

RAPAMYCIN

(also known as sirolimus). A peptide from the bacterium Streptomyces hygroscopicus, isolated from the soil on Easter Island. It is an inhibitor of Tor activity and functions as a potent immunosuppressant.

β-OXIDATION

A metabolic process in the mitochondria that uses fatty acids as substrates. The pathway consists of a repeating cycle of four reactions that yield acetyl CoA and reduced electron carriers. It is a source of both ATP and oxidizable substrates.

CAP-DEPENDENT TRANSLATION

Protein translation of mRNAs that are capped with 7-methyl-guanine.

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Lum, J., DeBerardinis, R. & Thompson, C. Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 6, 439–448 (2005). https://doi.org/10.1038/nrm1660

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