Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis
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Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.
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Recent work shows that the anti-tumorigenic effect of metformin can be at least partially accounted for by direct mitochondrial complex I inhibition in tumors.
“Although the precise mechanism of metformin action remains controversial (Luengo et al., 2014), recent work has shown that the anti-tumorigenic effect of metformin can at least be partially accounted for by direct mitochondrial complex I inhibition in tumors (Gui et al., 2016; Wheaton et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Wheaton et al., 2014
Metformin's anti-tumor effects occur through inhibition of mitochondrial complex I.
“It is not clear what the target of metformin in immune cells is but the anti-tumor effects of metformin are through inhibiting mitochondrial complex I (Wheaton et al., 2014).”
From Mitochondria in the Regulation of Innate and Adaptive Immunity (2015) · cites this paper as Wheaton et al., 2014
It has been argued that inhibition of mitochondrial complex 1 is an important contributor to the cytotoxic effects of metformin and has been observed in cancer cells and supported by data showing reduced inhibition of tumor growth in cancer cells expressing a metformin-resistant yeast complex 1, NDI1.
“It has also been argued that the inhibition of mitochondrial complex 1 is an important contributor to the cytotoxic effects of metformin and has been observed in cancer cells and supported by data showing reduced inhibition of tumor growth in cancer cells expressing a metformin-resistant yeast complex 1, NDI1 (136, 243).”
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 [243]
Metformin alleviates tumor hypoxia by reducing oxygen consumption by inhibiting complex I in the mitochondrial electron transport chain.
“In addition, studies have shown that metformin (Met), a typical antidiabetic drug, also alleviates tumor hypoxia by reducing oxygen consumption by inhibiting complex I in the mitochondrial electron transport chain.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [278]
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- Authors
- Wheaton, W. W., Weinberg, S. E., Hamanaka, R. B., Soberanes, S., Sullivan, L. B., Anso, E., Glasauer, A., Dufour, E., Mutlu, G. M., Budigner, G. S., & Chandel, N. S.
- Affiliations
- Northwestern University (US)
- Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States
- Institute of Biomedical Technology, University of Tampere, Tampere, Finland
- Corresponding author
- Chandel, Navdeep S
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2014-05-13
- Volume
- 3
- Pages
- e02242-e02242
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4017650
- OpenAlex
- W2119437574
- Cited by
- 1,105
- References
- 51
- Citations by year
- 2026: 54 · 2025: 84 · 2024: 86 · 2023: 106 · 2022: 104 · 2021: 125 · 2020: 113 · 2019: 125 · 2018: 92 · 2017: 85 · 2016: 60 · 2015: 56 · 2014: 13
- FWCI
- 29.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Tampere University Institutional Repository (Tampere University) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (RO1 CA123067, T32GM08061, T32HL076139)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- metformin, mitochondrial complex I, NADH dehydrogenase, tumor cell proliferation, cellular respiration, glycolysis, glucose deprivation, hypoxia, HIF-1, NDI1, drug resistance, carcinogenesis, cancer prevention
- MeSH terms
- Humans, Metformin, Neoplasms, Electron Transport Complex I, Cell Line, Tumor, Carcinogenesis
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