Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly
Open accessAbstract
Mitochondrial reactive oxygen species (ROS) production is a tightly regulated redox signal that transmits information from the organelle to the cell. Other mitochondrial signals, such as ATP, are sensed by enzymes, including the key metabolic sensor and regulator, AMP-activated protein kinase (AMPK). AMPK responds to the cellular ATP/AMP and ATP/ADP ratios by matching mitochondrial ATP production to demand. Previous reports proposed that AMPK activity also responds to ROS, by ROS acting on redox-sensitive cysteine residues (Cys-299/Cys-304) on the AMPK α subunit. This suggests an appealing model in which mitochondria fine-tune AMPK activity by both adenine nucleotide–dependent mechanisms and by redox signals. Here we assessed whether physiological levels of ROS directly alter AMPK activity. To this end we added exogenous hydrogen peroxide (H 2 O 2 ) to cells and utilized the mitochondria-targeted redox cycler MitoParaquat to generate ROS within mitochondria without disrupting oxidative phosphorylation. Mitochondrial and cytosolic thiol oxidation was assessed by measuring peroxiredoxin dimerization and by redox-sensitive fluorescent proteins. Replacing the putative redox-active cysteine residues on AMPK α1 with alanines did not alter the response of AMPK to H 2 O 2 . In parallel with measurements of AMPK activity, we measured the cell ATP/ADP ratio. This allowed us to separate the effects on AMPK activity due to ROS production from those caused by changes in this ratio. We conclude that AMPK activity in response to redox changes is not due to direct action on AMPK itself, but is a secondary consequence of redox effects on other processes, such as mitochondrial ATP production.
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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 [44]
Exposure of exogenous hydrogen peroxide to C2C12 cells led to a dose-dependent increase in AMPK activity by decreasing the ATP-to-ADP ratio.
“For instance, exposure of exogenous hydrogen peroxide to C2C12 cells led to a dose-dependent increase in AMPK activity by decreasing the ATP-to-ADP ratio [44].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [44]
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- Authors
- Hinchy, E. C., Gruszczyk, A. V., Willows, R., Navaratnam, N., Hall, A. R., Bates, G., Bright, T. P., Krieg, T., Carling, D., & Murphy, M. P.
- Affiliations
- University of Cambridge (GB)
- Hammersmith Hospital (GB)
- Corresponding author
- Murphy, Michael P.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 293
- Issue
- 44
- Pages
- 17208-17217
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6222118
- OpenAlex
- W2891220313
- Cited by
- 302
- References
- 44
- Citations by year
- 2026: 25 · 2025: 38 · 2024: 37 · 2023: 26 · 2022: 47 · 2021: 50 · 2020: 55 · 2019: 22 · 2018: 2
- FWCI
- 11.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- RCUK MRC Medical Research Foundation (MC_UU_00015/3)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- AMPK, mitochondrial reactive oxygen species, hydrogen peroxide, redox signaling, thiol oxidation, ATP/ADP ratio, mitochondrial ATP production, oxidative phosphorylation
- MeSH terms
- Adenosine Diphosphate, Adenosine Triphosphate, Animals, Cell Line, Enzyme Activation, Humans, Hydrogen Peroxide, Mitochondria, Oxidation-Reduction, Reactive Oxygen Species, Muscle Fibers, Skeletal, Mice, AMP-Activated Protein Kinases
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