The AMP‐Activated Protein Kinase: Fuel Gauge of the Mammalian Cell?
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A single entity, the AMP-activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutaryl-CoA reductase and acetyl-CoA carboxylase (key regulatory enzymes of sterol synthesis and fatty acid synthesis, respectively), and probably many additional targets. The kinase is activated by high AMP and low ATP via a complex mechanism, which involves allosteric regulation, promotion of phosphorylation by an upstream protein kinase (AMPK kinase), and inhibition of dephosphorylation. This protein-kinase cascade represents a sensitive system, which is activated by cellular stresses that deplete ATP, and thus acts like a cellular fuel gauge. Our central hypothesis is that, when it detects a 'low-fuel' situation, it protects the cell by switching off ATP-consuming pathways (e.g. fatty acid synthesis and sterol synthesis) and switching on alternative pathways for ATP generation (e.g. fatty acid oxidation). Native AMP-activated protein kinase is a heterotrimer consisting of a catalytic alpha subunit, and beta and gamma subunits, which are also essential for activity. All three subunits have homologues in budding yeast, which are components of the SNF1 protein-kinase complex. SNF1 is activated by glucose starvation (which in yeast leads to ATP depletion) and genetic studies have shown that it is involved in derepression of glucose-repressed genes. This raises the intriguing possibility that AMPK may regulate gene expression in mammals. AMPK/SNF1 homologues are found in higher plants, and this protein-kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress.
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AMPK functions as an energy sensor that coordinates multiple protective and energy-conserving signaling pathways including the pathways activated by caloric restriction.
“AMPK functions as an energy sensor that coordinates multiple protective and energy-conserving signaling pathways including the pathways activated by caloric restriction and referred to as the fuel gauge of the cell by serving as an energy sensor (100, 101) (Figure 1).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [100]
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- Authors
- Hardie, D. G., & Carling, D.
- Affiliations
- University of Dundee (GB)
- Hammersmith Hospital (GB)
- Corresponding author
- Hardie, D. Grahame
- Venue
- European Journal of Biochemistry
- Publisher
- Wiley
- Published
- 1997-06
- Volume
- 246
- Issue
- 2
- Pages
- 259-273
- ISSN
- 0014-2956 (ISSN-L)
- 1432-1033
- OpenAlex
- W1565979608
- Cited by
- 1,317
- References
- 154
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 22 · 2023: 16 · 2022: 35 · 2021: 52 · 2020: 31 · 2019: 30 · 2018: 33 · 2017: 35 · 2016: 50 · 2015: 43 · 2014: 39 · 2013: 43 · 2012: 71
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- 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 › Protein Kinase Regulation and GTPase Signaling
- Keywords
- AMPK, hydroxymethylglutaryl-CoA reductase, acetyl-CoA carboxylase, sterol biosynthesis, fatty acid synthesis, allosteric regulation, ATP depletion, Snf1 kinase, glucose deprivation, gene expression regulation, evolutionary conservation, nutritional stress
- MeSH terms
- Amino Acid Sequence, Animals, Energy Metabolism, Molecular Sequence Data, Multienzyme Complexes, Protein Kinases, Substrate Specificity, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, AMP-Activated Protein Kinases
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