AMPK: guardian of metabolism and mitochondrial homeostasis

Key Points

  • AMP-activated protein kinase (AMPK) is a highly conserved sensor of low intracellular ATP levels that is rapidly activated after nearly all mitochondrial stresses, even those that do not disrupt the mitochondrial membrane potential.

  • Upon changes in the ATP-to-AMP ratio, AMPK is activated and phosphorylates downstream targets to redirect metabolism towards increased catabolism and decreased anabolism.

  • AMPK regulates autophagy and mitophagy through activation of the kinase ULK1, the mammalian homologue of ATG1.

  • AMPK phosphorylates mitochondrial fission factor and promotes mitochondrial fission upon energetic stress.

  • By simultaneously regulating mitochondrial fission, mitophagy and transcriptional control of mitochondrial biogenesis, AMPK acts as a signal integration platform to maintain mitochondrial health.

  • AMPK also controls transcriptional regulators of autophagy and lysosomal genes.

Abstract

Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy. This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

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Figure 1: AMPK structure and activation.
Figure 2: AMPK regulates a variety of metabolic processes.
Figure 3: Regulation of mitochondrial homeostasis by AMPK.
Figure 4: Details of the regulation of autophagy by mTOR, AMPK and ULK1.
Figure 5: Modulation of the transcription of autophagy and lysosome genes by AMPK.

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Acknowledgements

S.H. is supported by an Advanced PostDoc.Mobility fellowship of the Swiss National Science Foundation. R.J.S. holds the William R. Brody Chair. The work from the authors' laboratory described in this Review was supported by grants from the US National Institutes of Health (R01DK080425, R01CA172229, P01CA120964) and The Leona M. and Harry B. Helmsley Charitable Trust (grant #2012-PGMED002).

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S.H. and R.J.S. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Correspondence to Reuben J. Shaw.

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The authors declare no competing financial interests.

PowerPoint slides

Glossary

Allosteric mechanism

Modulation of protein activity by the binding of a molecule to a specific site, often associated with a change in conformation.

Axin

A protein involved in WNT pathway signalling regulation and in mTOR signalling at the lysosome.

Acetyl-CoA carboxylases

Enzymes that catalyse the first step in de novo lipid synthesis, the carboxylation of acetyl-CoA to malonyl-CoA.

Metformin

A widely prescribed type 2 diabetes drug. Mechanistically, metformin inhibits complex I of the respiratory chain and leads to changes in the ATP-to-AMP ratio and activation of AMP-activated protein kinase (AMPK).

Mitophagy

Specific removal of mitochondria by autophagy.

Complex I and complex III

Complexes of the respiratory chain in the mitochondrial inner membrane that couple the transfer of electrons to proton pumping. The proton gradient created by the respiratory chain is used to produce ATP, while the electrons are transferred to molecular oxygen.

Dynamin-like protein DRP1

A protein necessary for mitochondrial fission. DRP1 is recruited to mitochondria at sites of future division and mediates the constriction of mitochondria.

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Herzig, S., Shaw, R. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19, 121–135 (2018). https://doi.org/10.1038/nrm.2017.95

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