The classical role of AMP-activated protein kinase (AMPK) is as a cellular energy sensor activated by falling energy status, signalled by increases in AMP to ATP and ADP to ATP ratios. Once activated, AMPK acts to restore energy homeostasis by promoting ATP-producing catabolic pathways while inhibiting energy-consuming processes. In this Review, we provide an update on this canonical (AMP/ADP-dependent) activation mechanism, but focus mainly on recently described non-canonical pathways, including those by which AMPK senses the availability of glucose, glycogen or fatty acids and by which it senses damage to lysosomes and nuclear DNA. We also discuss new findings on the regulation of carbohydrate and lipid metabolism, mitochondrial and lysosomal homeostasis, and DNA repair. Finally, we discuss the role of AMPK in cancer, obesity, diabetes, nonalcoholic steatohepatitis (NASH) and other disorders where therapeutic targeting may exert beneficial effects.
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Recent studies in the D.G.H. laboratory have been funded by an Investigator Award from the Welcome Trust (204766/Z/16/Z) and a Programme Grant (C37030/A15101) from Cancer Research UK. G.R.S. is supported by research grants from the Canadian Institutes of Health Research (201709FDN-CEBA-116200), Diabetes Canada (DI-5-17-5302), a Tier 1 Canada Research Chair and a J. Bruce Duncan Endowed Chair in Metabolic Diseases.
D.G.H. declares no competing interests. G.R.S. has received research funding from Esperion Therapeutics, Espervita Therapeutics, Poxel Pharmaceuticals, Nestle, Novo Nordisk and Rigel Pharmaceuticals; honoraria and/or consulting fees from AstraZeneca, Cambrian BioPharma, EcoR1 Capital, Eli-Lilly, Esperion Therapeutics, Fibrocor Therapeutics, Pfizer, Poxel Pharmaceuticals and Merck; and is a founder and shareholder of Espervita Therapeutics.
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- Activation loop
A flexible loop in the carboxy-terminal lobe (C-lobe) of protein kinase domains whose conformation is crucial for substrate binding and catalysis; many protein kinases require phosphorylation within this loop to become active.
- Allosteric drug and metabolite (ADaM) site
A ligand-binding site on AMP-activated protein kinase (AMPK), located between the β-carbohydrate-binding module (β-CBM) and the amino-terminal lobe (N-lobe) of the α-kinase domain (α-KD), which binds long-chain fatty acyl-CoA esters and certain pharmacological activators of AMPK.
A small protein that is a major sensor of intracellular Ca2+, binding of which causes calmodulin to bind to and activate other proteins.
- Catalytic module
The portion of the AMP-activated protein kinase (AMPK) heterotrimer containing the α-kinase domain (α-KD) and (at least in some situations) the β-carbohydrate-binding module (β-CBM).
- CBS repeats
(Cystathionine-β-synthase repeats). Sequence motifs of ≈60 amino acids first recognized in the enzyme cystathionine β-synthase; they occur as tandem repeats forming pseudo-dimers that bind regulatory ligands, usually containing adenosine.
Protein kinases often phosphorylate themselves (autophosphorylation); it is defined as cis when it is an intramolecular event, occurring within a single molecule of the kinase.
- E3 ubiquitin ligases
Enzymes that attach polymerized chains of the protein ubiquitin to another protein, often (but not always) targeting the latter for degradation.
A type of programmed cell death that is dependent on iron and characterized by the accumulation of lipid peroxides.
A hormone released from the gastrointestinal tract (particularly the stomach) under conditions of fasting, which promotes appetite by effects on the hypothalamus in the brain.
- Homologous recombination
A DNA repair mechanism in which the sequence affected is copied using the homologous chromosome as a template, which is much more accurate than non-homologous end joining.
(IP3). A soluble second messenger released inside cells in response to many hormones and growth factors, which triggers release of cytosolic Ca2+ by binding to IP3 receptors on the endoplasmic reticulum.
Autophagic removal of lysosomes that are damaged or surplus to requirements.
- Lysosomal v-ATPase
The lysosomal, ATP-driven proton pump that maintains the pH of the lysosomal lumen lower than that of the cytoplasm, allowing lysosomal digestive enzymes with acid pH optima to remain active.
- Lysosomotropic agents
Substances that are taken up selectively into lysosomes.
Small single-stranded non-coding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression.
- Mitochondrial uncoupling
The respiratory chain pumps protons out across the inner mitochondrial membrane, creating a gradient of protons that drives ATP synthesis as they return across the inner membrane via the ATP synthase complex. Uncoupling, which inhibits ATP synthesis, is the removal of the tight linkage between these processes, for example, by chemicals that transport protons, thus collapsing the proton gradient, independently of the ATP synthase.
Autophagic removal of damaged mitochondrial segments.
- Non-homologous end joining
A DNA repair mechanism in which the broken ends are directly ligated without the need for a homologous template, which is less accurate than homologous recombination.
- Nuclear export signals
(NESs). Sequence motifs in a protein that are involved, by binding to exportins involved in nuclear export, in translocation of the protein from the nucleus to the cytoplasm.
- Ragulator complex
A complex of 5 proteins (LAMTOR1–5) that are associated with the lysosome and involved with the reciprocal regulation of mTORC1 and AMPK.
- Regulatory module
The portion of the AMP-activated protein kinase (AMPK) heterotrimer containing the α-carboxy-terminal domain (α-CTD), the β-C-terminal region (β-CTR) and the entire γ-subunit.
- Ribonuclease reductase
The enzyme that converts ribonucleotides to deoxyribonucleotides, which is essential for DNA synthesis and is inhibited by hydroxyurea.
- ST loops
Serine/threonine-rich sequences present near the carboxy termini of the α1-subunits and α2-subunits of AMP-activated protein kinase (AMPK) in vertebrates, but not in unicellular eukaryotes; they can be phosphorylated at multiple sites.
- Store-operated Ca2+ entry
A mechanism by which depletion of Ca2+ in the endoplasmic reticulum (for example, caused by activation of inositol-1,4,5-trisphosphate (IP3) receptors) triggers opening of Ca2+ channels in the plasma membrane; it involves interactions between the endoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1) and the plasma membrane Ca2+ channel, ORAI1.
- Vascular endothelial growth factor
(VEGF). A growth factor released from hypoxic tissues (including tumour tissue) that promotes the growth of new blood vessels (angiogenesis).
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Steinberg, G.R., Hardie, D.G. New insights into activation and function of the AMPK. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00547-x