Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK Activation
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A wide variety of agents activate AMPK, but in many cases the mechanisms remain unclear. We generated isogenic cell lines stably expressing AMPK complexes containing AMP-sensitive (wild-type, WT) or AMP-insensitive (R531G) gamma2 variants. Mitochondrial poisons such as oligomycin and dinitrophenol only activated AMPK in WT cells, as did AICAR, 2-deoxyglucose, hydrogen peroxide, metformin, phenformin, galegine, troglitazone, phenobarbital, resveratrol, and berberine. Excluding AICAR, all of these also inhibited cellular energy metabolism, shown by increases in ADP:ATP ratio and/or by decreases in cellular oxygen uptake measured using an extracellular flux analyzer. By contrast, A769662, the Ca(2+) ionophore, A23187, osmotic stress, and quercetin activated both variants to varying extents. A23187 and osmotic stress also increased cytoplasmic Ca(2+), and their effects were inhibited by STO609, a CaMKK inhibitor. Our approaches distinguish at least six different mechanisms for AMPK activation and confirm that the widely used antidiabetic drug metformin activates AMPK by inhibiting mitochondrial respiration.
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In HEK293 cells expressing AMPKγ2 R531G, an AMP-insensitive AMPK complex, AMPK cannot be activated by hydrogen peroxide.
“Further, using HEK293 cells expressing AMPKγ2 R531G, an AMP-insensitive AMPK complex, AMPK cannot be activated by hydrogen peroxide [46].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [46]
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 [46]
Quercetin activates AMPK and SIRT1.
“Indeed, this polyphenol has been reported to activate the AMPK and SIRT1 (Howitz et al., 2003; Hawley et al., 2010)”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Hawley et al., 2010
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AMPK: positive and negative regulation, and its role in whole-body energy homeostasis
Hardie, D. G. (2015) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2014.09.004 · Cited by 485 · see citing works
Self-citationMolecular mechanism of action of metformin: old or new insights?
Rena, G., Pearson, E. R., & Sakamoto, K. (2013) · Diabetologia · doi:10.1007/s00125-013-2991-0 · Cited by 479 · see citing works
The molecular targets of resveratrol
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“[74], which refutes a significant role for the Ca–CAMKKβ pathway.”
AMPK: A Target for Drugs and Natural Products With Effects on Both Diabetes and Cancer
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Self-citationMetformin Action: Concentrations Matter
He, L., & Wondisford, F. E. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.01.003 · Cited by 448 · see citing works
Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase
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Targeting Sirtuin 1 to Improve Metabolism: All You Need Is NAD+?
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Metformin Activates a Duodenal Ampk-Dependent Pathway to Lower Hepatic Glucose Production in Rats
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Sensing of energy and nutrients by AMP-activated protein kinase
Hardie, D. G. (2011) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.110.001925 · Cited by 372 · see citing works
Self-citationAMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity.
O’Neill, H. M., Holloway, G. P., & Steinberg, G. R. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.019 · Cited by 364 · see citing works
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Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy
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Unraveling the regulation of hepatic gluconeogenesis
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Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase
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Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier
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Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly
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Grahame Hardie, D. (2014) · Journal of Internal Medicine · doi:10.1111/joim.12268 · Cited by 285 · see citing works
AMPK, Mitochondrial Function, and Cardiovascular Disease
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Repurposing metformin: an old drug with new tricks in its binding pockets
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Calorie Restriction: Is AMPK a Key Sensor and Effector
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AMP-activated protein kinase regulation and biological actions in the heart
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AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels
Hardie, D. G. (2014) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161148 · Cited by 281 · see citing works
Self-citationAging Hallmarks: The Benefits of Physical Exercise
Rebelo-Marques, A., De Sousa Lages, A., Andrade, R., Ribeiro, C. F., Mota-Pinto, A., Carrilho, F., & Espregueira-Mendes, J. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00258 · Cited by 246 · see citing works
Metformin and Other Biguanides in Oncology: Advancing the Research Agenda
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Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition
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Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions
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Resveratrol as a calorie restriction mimetic: therapeutic implications
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Mitochondrial dysfunction and complications associated with diabetes
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Phosphorylation of AMPK by upstream kinases is required for activity in mammalian cells
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AMP-activated protein kinase: Also regulated by ADP?
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Self-citationDifferential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms
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Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism
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Self-citationExercise and mitochondrial dynamics: keeping in shape with ROS and AMPK
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AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase
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Metabolic effects of resveratrol: Addressing the controversies
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Translation Regulation as a Therapeutic Target in Cancer
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Targeting LKB1 in Cancer – Exposing and Exploiting Vulnerabilities
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- Authors
- Hawley, S. A., Ross, F. A., Chevtzoff, C., Green, K. A., Evans, A., Fogarty, S., Towler, M. C., Brown, L. J., Ogunbayo, O. A., Evans, A. M., & Hardie, D. G.
- Affiliations
- University of Dundee (GB)
- University of Edinburgh (GB)
- Corresponding author
- Hardie, D. Grahame
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 11
- Issue
- 6
- Pages
- 554-565
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2935965
- OpenAlex
- W1966706887
- Cited by
- 773
- References
- 65
- Citations by year
- 2026: 22 · 2025: 31 · 2024: 39 · 2023: 36 · 2022: 45 · 2021: 50 · 2020: 42 · 2019: 43 · 2018: 53 · 2017: 53 · 2016: 58 · 2015: 51 · 2014: 60 · 2013: 60 · 2012: 68
- FWCI
- 24.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Keywords
- AMPK activation, isogenic cell lines, metformin, mitochondrial respiration, AICAR, ATP/ADP ratio, calcium signaling, CaMKK, resveratrol, berberine, troglitazone, phenobarbital, energy metabolism
- MeSH terms
- Calcimycin, Adenosine Diphosphate, Adenosine Triphosphate, Anti-Bacterial Agents, Benzimidazoles, Calcium, Cell Line, Dinitrophenols, Energy Metabolism, Enzyme Activation, Humans, Hypoglycemic Agents, Metformin, Oligomycins, Phosphorylation, Protein Subunits, Naphthalimides, AMP-Activated Protein Kinases
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