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AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs
Open accessAbstract
AMP-activated protein kinase (AMPK) is a key regulator of energy balance expressed ubiquitously in eukaryotic cells. Here we review the canonical adenine nucleotide-dependent mechanism that activates AMPK when cellular energy status is compromised, as well as other, noncanonical activation mechanisms. Once activated, AMPK acts to restore energy homeostasis by promoting catabolic pathways, resulting in ATP generation, and inhibiting anabolic pathways that consume ATP. We also review the various hypothesis-driven and unbiased approaches that have been used to identify AMPK substrates and have revealed substrates involved in both metabolic and non-metabolic processes. We particularly focus on methods for identifying the AMPK target recognition motif and how it can be used to predict new substrates.
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“AMPK is a heterotrimeric serine/threonine kinase composed of a catalytic α subunit (PRKAA1), which is essential for AMPK function through phosphorylation of its activation loop, and regulatory β and γ subunits [12].”
From AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma (2021) · cites this paper as [12]
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“Aerobic exercise activates AMPK, particularly under low energy availability conditions, as it restores energy balance by increasing glucose uptake and fatty acid oxidation [226,227].”
From Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR) (2025) · cites this paper as [227]
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“Aerobic exercise activates AMPK, particularly under low energy availability conditions, as it restores energy balance by increasing glucose uptake and fatty acid oxidation [226,227].”
From Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR) (2025) · cites this paper as [227]
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Self-citation3’UTR-dependent dynamic changes in TP53 mRNA localization regulate p53 tumor suppressor activityPreprint
Hu, L., Misra, S., Karim, B. O., Kuhn, S. A., Salotti, J., Basu, S., Martín, N. C. R., Saylor, K. L., & Johnson, P. F. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.04.487038
Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer
Ata, R., & Antonescu, C. N. (2021) · doi:10.32920/14639496
Zhang, L., Zhang, X., Wang, L., Yang, W., Qiao, Y., & Li, Q. (2020) · Research Square · doi:10.21203/rs.3.rs-48445/v1
Leib, D., & Manivanh, R. V. (2018) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727582977.793533719
The AMPK Activator A-769662 Inhibits Human TASK-3 Potassium Channels in an AMPK-Independent MannerPreprint
Said, E. A., Lewis, R. W., Dallas, M. L., Peers, C., Ross, F. A., Hardie, D. G., & Evans, A. M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.24.493214
Self-citationQu, S., Zhang, K., Jin, N., Li, H., & Nie, B. (2022) · Molecular & Cellular Toxicology · doi:10.1007/s13273-022-00298-y
Inhibition of Type I PRMTs Reforms Muscle Stem Cell Identity Enhancing their Therapeutic CapacityPreprint
Dominici, C., Villarreal, O. D., Dort, J., Heckel, É., Wang, Y. C., Ragoussis, I., Joyal, J., Dumont, N. A., & Richard, S. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.03.522550
Metadata
- Authors
- Hardie, D. G., Schaffer, B. E., & Brunet, A.
- Affiliations
- University of Dundee (GB)
- Stanford University (US)
- Corresponding author
- Hardie, D. Grahame
- Venue
- Trends in Cell Biology
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 26
- Issue
- 3
- Pages
- 190-201
- ISSN
- 0962-8924 (ISSN-L)
- PMC
- PMC5881568
- OpenAlex
- W2174118934
- Cited by
- 859
- References
- 75
- Citations by year
- 2026: 41 · 2025: 62 · 2024: 80 · 2023: 69 · 2022: 89 · 2021: 112 · 2020: 97 · 2019: 77 · 2018: 103 · 2017: 80 · 2016: 46
- FWCI
- 7.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Trends in Cell Biology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by-nc-nd)
- Funders
- Wellcome Trust (097726)
- Cancer Research UK (C37030/A15101)
- CIRM (RB4-06087)
- NIH (R01 AG031198, T32 CA09302)
- NSF GRFP
- Robert M. and Anne T. Bass Stanford Graduate Fellowship
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- AMPK, AMPK activation, energy homeostasis, catabolic pathways, ATP production, substrate recognition motif, substrate prediction
- MeSH terms
- Allosteric Regulation, Amino Acid Sequence, Animals, Energy Metabolism, Enzyme Activation, Humans, Phosphorylation, Protein Processing, Post-Translational, Signal Transduction, Catalytic Domain, AMP-Activated Protein Kinases
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