AMPK maintains cellular metabolic homeostasis through regulation of mitochondrial reactive oxygen species
Open accessAbstract
Reactive oxygen species (ROS) are continuously produced as a by-product of mitochondrial metabolism and eliminated via antioxidant systems. Regulation of mitochondrially produced ROS is required for proper cellular function, adaptation to metabolic stress, and bypassing cellular senescence. Here, we report non-canonical regulation of the cellular energy sensor AMP-activated protein kinase (AMPK) by mitochondrial ROS (mROS) that functions to maintain cellular metabolic homeostasis. We demonstrate that mitochondrial ROS are a physiological activator of AMPK and that AMPK activation triggers a PGC-1α-dependent antioxidant response that limits mitochondrial ROS production. Cells lacking AMPK activity display increased mitochondrial ROS levels and undergo premature senescence. Finally, we show that AMPK-PGC-1α-dependent control of mitochondrial ROS regulates HIF-1α stabilization and that mitochondrial ROS promote the Warburg effect in cells lacking AMPK signaling. These data highlight a key function for AMPK in sensing and resolving mitochondrial ROS for stress resistance and maintaining cellular metabolic balance.
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AMPK is responsive to imbalanced redox status.
“Recent lines of evidence have demonstrated AMPK responsiveness to imbalanced redox status, thus bringing new insights into the networks of redox-stimulated signals upstream of AMPK (Table 1) [42,43,44,45,46,47,48,49,50,51].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [51]
Addition of Trolox to mouse embryonic fibroblasts resulted in basal AMPK activity reduction, evidenced by decreased phosphor-AMPKα at Thr172.
“The addition of Trolox to mouse embryonic fibroblasts (MEFs) resulted in basal AMPK activity reduction, as evidenced by the decreased phosphor-AMPKα at Thr172 [51].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [51]
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- Authors
- Rabinovitch, R. C., Samborska, B., Faubert, B., Ma, E. H., Gravel, S.-P., Andrzejewski, S., Raissi, T. C., Pause, A., St.-Pierre, J., & Jones, R. G.
- Affiliations
- McGill University (CA)
- Corresponding author
- Jones, Russell G.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 21
- Issue
- 1
- Pages
- 1-9
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2761245997
- Cited by
- 543
- References
- 53
- Citations by year
- 2026: 43 · 2025: 44 · 2024: 55 · 2023: 70 · 2022: 75 · 2021: 88 · 2020: 75 · 2019: 54 · 2018: 33 · 2017: 5
- FWCI
- 18.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- McGill Integrated Cancer Research Training Program (MICRTP
- Fonds de la Recherche du Québec – Santé (FRQS
- Canadian Institutes of Health Research (CIHR
- CIHR (MOP-93799)
- Terry Fox Research Institute (TFRI-239585)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- AMPK, mitochondrial reactive oxygen species, metabolic homeostasis, PGC-1α, antioxidant response, cellular senescence, HIF-1α stabilization, Warburg effect, mitochondrial metabolism, energy sensing
- MeSH terms
- Autophagy-Related Protein-1 Homolog, Uncoupling Protein 2, Uncoupling Protein 3, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Superoxide Dismutase-1, Glutathione Peroxidase GPX1, Superoxide Dismutase 2, Animals, Fibroblasts, Gene Expression Regulation, Glutathione Peroxidase, Homeostasis, Humans, Mice, Transgenic, Mitochondria, Superoxide Dismutase, Signal Transduction, Cellular Senescence, Reactive Oxygen Species, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Metabolic Networks and Pathways, AMP-Activated Protein Kinases, Protein Stability, HEK293 Cells, Primary Cell Culture
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