Paracelsus Medizinische Privatuniversität (PMU)

Forschung & Innovation
Publikationen

The metabolic sensor AMPK

#2024
#MOLECULAR METABOLISM

PMU Autor*innen
William J. Smiles, Barbara Kofler

Alle Autor*innen
William J. Smiles, Ashley J. Ovens, Jonathan S. Oakhill, Barbara Kofler

Fachzeitschrift
MOLECULAR METABOLISM

Kurzfassung

Background: AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of energy metabolism. AMPK is sensitive to acute perturbations to cellular energy status and leverages fundamental bioenergetic pathways to maintain cellular homeostasis. AMPK is a heterotrimer comprised of a(3y-subunits that in humans are encoded by seven individual genes (isoforms a1, a2, (31, (32, y1, y2 and y3), permitting formation of at least 12 different complexes with personalised biochemical fingerprints and tissue expression patterns. While the canonical activation mechanisms of AMPK are well-defined, delineation of subtle, as well as substantial, differences in the regulation of heterogenous AMPK complexes remain poorly defined. Scope of review: Here, taking advantage of multidisciplinary findings, we dissect the many aspects of isoform-specific AMPK function and links to health and disease. These include, but are not limited to, allosteric activation by adenine nucleotides and small molecules, co-translational myristoylation and post-translational modifications (particularly phosphorylation), governance of subcellular localisation, and control of transcriptional networks. Finally, we delve into current debate over whether AMPK can form novel protein complexes (e.g., dimers lacking the asubunit), altogether highlighting opportunities for future and impactful research. Major conclusions: Baseline activity of a1-AMPK is higher than its a2 counterpart and is more sensitive to synergistic allosteric activation by metabolites and small molecules. a2 complexes however, show a greater response to energy stress (i.e., AMP production) and appear to be better substrates for LKB1 and mTORC1 upstream. These differences may explain to some extent why in certain cancers a1 is a tumour promoter and a2 a suppressor. (31-AMPK activity is toggled by a 'myristoyl-switch' mechanism that likely precedes a series of signalling events culminating in phosphorylation by ULK1 and sensitisation to small molecules or endogenous ligands like fatty acids. (32-AMPK, not entirely beholden to this myristoyl-switch, has a greater propensity to infiltrate the nucleus, which we suspect contributes to its oncogenicity in some cancers. Last, the unique N-terminal extensions of the y2 and y3 isoforms are major regulatory domains of AMPK. mTORC1 may directly phosphorylate this region in y2, although whether this is inhibitory, especially in disease states, is unclear. Conversely, y3 complexes might be preferentially regulated by mTORC1 in response to physical exercise. (c) 2024 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Keywords

CANCER, EXERCISE, METABOLISM, AMPK, Signalling, mTORC1