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Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria
Open accessAbstract
The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of mitochondrial respiratory complex I by metformin is the primary cause of its cell-lineage-specific actions and therapeutic effects, the molecular interaction(s) between metformin and complex I remain uncharacterized. In the present paper, we describe the effects of five pharmacologically relevant biguanides on oxidative phosphorylation in mammalian mitochondria. We report that biguanides inhibit complex I by inhibiting ubiquinone reduction (but not competitively) and, independently, stimulate reactive oxygen species production by the complex I flavin. Biguanides also inhibit mitochondrial ATP synthase, and two of them inhibit only ATP hydrolysis, not synthesis. Thus we identify biguanides as a new class of complex I and ATP synthase inhibitor. By comparing biguanide effects on isolated complex I and cultured cells, we distinguish three anti-diabetic and potentially anti-neoplastic biguanides (metformin, buformin and phenformin) from two anti-malarial biguanides (cycloguanil and proguanil): the former are accumulated into mammalian mitochondria and affect oxidative phosphorylation, whereas the latter are excluded so act only on the parasite. Our mechanistic and pharmacokinetic insights are relevant to understanding and developing the role of biguanides in new and existing therapeutic applications, including cancer, diabetes and malaria.
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“inhibition of mitochondrial complex 1 in the electron transport chain and reduction of endogenous production of reactive oxygen species (ROS) (Batandier et al., 2006; Bridges et al., 2014; Zheng et al., 2012)”
From Metformin as a tool to target aging (2016) · cites this paper as Bridges et al., 2014
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“inhibition of mitochondrial complex 1 in the electron transport chain and reduction of endogenous production of reactive oxygen species (ROS) (Batandier et al., 2006; Bridges et al., 2014; Zheng et al., 2012)”
From Metformin as a tool to target aging (2016) · cites this paper as Bridges et al., 2014
In the citing paper
“However, metformin, one of the commonly prescribed drugs for treating type II diabetes, is safe despite acting as a mitochondrial complex I inhibitor that impairs respiration (Bridges et al., 2014; El-Mir et al., 2000; Owen et al., 2000; Wheaton et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Bridges et al., 2014
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“It is also worthy of note that the IC50 for metformin to inhibit mitochondrial complex 1 is 19–66 mM (140, 141).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [141]
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Metadata
- Authors
- Bridges, H. R., Jones, A. J. Y., Pollak, M. N., & Hirst, J.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- Department of Oncology, McGill University and Lady Davis Research Institute of the Jewish General Hospital, Montreal, Quebec, Canada, H3T 1E2
- Corresponding author
- Hirst, Judy
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2014-08-22
- Volume
- 462
- Issue
- 3
- Pages
- 475-487
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC4148174
- OpenAlex
- W2012442095
- Cited by
- 661
- References
- 79
- Citations by year
- 2026: 30 · 2025: 53 · 2024: 45 · 2023: 41 · 2022: 61 · 2021: 95 · 2020: 72 · 2019: 66 · 2018: 64 · 2017: 60 · 2016: 43 · 2015: 22 · 2014: 9
- FWCI
- 18.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Medical Research Council (U105663141)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- metformin, biguanides, oxidative phosphorylation, mitochondrial complex I, ubiquinone reduction, reactive oxygen species, ATP synthase inhibition, buformin, phenformin, cycloguanil, proguanil, mitochondrial accumulation, type 2 diabetes, anticancer activity, malaria
- MeSH terms
- Animals, Antimalarials, Antineoplastic Agents, Biguanides, Cattle, Proguanil, Diabetes Mellitus, Type 2, Humans, Metformin, Mitochondria, Heart, Mitochondria, Liver, Oxidative Phosphorylation, Plasmodium, Triazines, Reperfusion Injury, Mitochondrial Proton-Translocating ATPases, Electron Transport Complex I, Rats, Hep G2 Cells
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