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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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1 retracted
Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo
Zou, M., Kirkpatrick, S. S., Davis, B. J., Nelson, J. S., Wiles, W. G., Schlattner, U., Neumann, D., Brownlee, M., Freeman, M. B., & Goldman, M. H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404421200 · Cited by 480
RetractedUnderstanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
How mitochondria produce reactive oxygen species
Murphy, M. P. (2009) · Biochemical Journal · doi:10.1042/bj20081386 · Cited by 8,207
Watterson, K. R., Bestow, D., Gallagher, J. R., Hamilton, D. L., Ashford, F. B., Meakin, P. J., & Ashford, M. L. J. (2012) · Neurosignals · doi:10.1159/000334144 · Cited by 3,395
OWEN, M. R., DORAN, E., & HALESTRAP, A. P. (2000) · Biochemical Journal · doi:10.1042/bj3480607 · Cited by 2,157
The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., & Cantley, L. C. (2005) · Science · doi:10.1126/science.1120781 · Cited by 1,950
Kinaan, M., Ding, H., & Triggle, C. R. (2015) · Medical Principles and Practice · doi:10.1159/000381643 · Cited by 1,515
El-Mir, M.-Y., Nogueira, V., Fontaine, E., Avéret, N., Rigoulet, M., & Leverve, X. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.1.223 · Cited by 1,399
Metformin—mode of action and clinical implications for diabetes and cancer
Pernicova, I., & Korbonits, M. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.256 · Cited by 1,393
Partial Resolution of the Enzymes Catalyzing Oxidative Phosphorylation
Kagawa, Y., & Racker, E. (1971) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)61930-1 · Cited by 1,361
Flagged first, then by citations
1 of the 79 references couldn’t be matched to a known paper.
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Sorted by citations
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
The mechanisms of action of metformin
Rena, G., Hardie, D. G., & Pearson, E. R. (2017) · Diabetologia · doi:10.1007/s00125-017-4342-z · Cited by 2,287
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Hart, T., Chandrashekhar, M., Aregger, M., Steinhart, Z., Brown, K. R., MacLeod, G., Mis, M., Zimmermann, M., Fradet-Turcotte, A., Sun, S., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.015 · Cited by 1,571
Zielonka, J., Joseph, J., Sikora, A., Hardy, M., Ouari, O., Vasquez-Vivar, J., Cheng, G., Lopez, M., & Kalyanaraman, B. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00042 · Cited by 1,683
Metformin: from mechanisms of action to therapies
Foretz, M., Guigas, B., Bertrand, L., Pollak, M., & Viollet, B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.09.018 · Cited by 1,501
Self-citationTargeting mitochondria metabolism for cancer therapy
Weinberg, S. E., & Chandel, N. S. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1712 · Cited by 1,420
Targeting cancer metabolism in the era of precision oncology
Stine, Z. E., Schug, Z. T., Salvino, J. M., & Dang, C. V. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00339-6 · Cited by 1,189
Metformin as a tool to target aging
Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.011 · Cited by 1,096
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971
An inhibitor of oxidative phosphorylation exploits cancer vulnerability
Molina, J. R., Sun, Y., Protopopova, M., Gera, S., Bandi, M., Bristow, C., McAfoos, T., Morlacchi, P., Ackroyd, J., Agip, A.-N. A., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0052-4 · Cited by 928
Self-citationCellular and Molecular Mechanisms of Metformin Action
LaMoia, T. E., & Shulman, G. I. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnaa023 · Cited by 791
Mitochondrial Metabolism as a Target for Cancer Therapy
Vasan, K., Werner, M., & Chandel, N. S. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.019 · Cited by 762
Metformin: update on mechanisms of action and repurposing potential
Foretz, M., Guigas, B., & Viollet, B. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00833-4 · Cited by 791
Anti-inflammatory effects of metformin irrespective of diabetes status
Cameron, A. R., Morrison, V. L., Levin, D., Mohan, M., Forteath, C., Beall, C., McNeilly, A. D., Balfour, D. J. K., Savinko, T., Wong, A. K. F., et al. (2016) · Circulation Research · doi:10.1161/circresaha.116.308445 · Cited by 704
Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus
Foretz, M., Guigas, B., & Viollet, B. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0242-2 · Cited by 686
Metformin-associated lactic acidosis: current perspectives on causes and risk
DeFronzo, R., Fleming, G. A., Chen, K., & Bicsak, T. A. (2016) · Metabolism · doi:10.1016/j.metabol.2015.10.014 · Cited by 658
Abdel-Wahab, A. F., Mahmoud, W., & Al-Harizy, R. M. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104511 · Cited by 598
Burgos‐Morón, E., Abad‐Jiménez, Z., Marañón, A., Iannantuoni, F., Escribano‐López, I., López‐Domènech, S., Salom, C., Jover, A., Llabata, V. M., Torres, I. R., et al. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8091385 · Cited by 612
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Wang, Y., An, H., Liu, T., Qin, C., Sesaki, H., Guo, S., Radovick, S., Hussain, M., Maheshwari, A., Wondisford, F. E., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.09.070 · Cited by 432
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BackgroundInfluentialMetformin directly acts on mitochondria to alter cellular bioenergetics
Andrzejewski, S., Gravel, S., Pollak, M., & St‐Pierre, J. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-12 · Cited by 437
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Pinti, M. V., Fink, G. K., Hathaway, Q. A., Durr, A. J., Kunovac, A., & Hollander, J. M. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00314.2018 · Cited by 447
Yap, T. A., Daver, N. G., Mahendra, M., Zhang, J., Kamiya-Matsuoka, C., Meric‐Bernstam, F., Kantarjian, H. M., Ravandi, F., Collins, M., Francesco, M. E. D., et al. (2023) · Nature Medicine · doi:10.1038/s41591-022-02103-8 · Cited by 426
Xian, H., Liu, Y., Nilsson, A. R., Gatchalian, R., Crother, T. R., Tourtellotte, W. G., Zhang, Y., Alemán-Muench, G. R., Lewis, G. M., Chen, W., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.05.004 · Cited by 412
Kordes, S., Pollak, M. N., Zwinderman, A. H., Mathôt, R. A., Weterman, M. J., Beeker, A., Punt, C. J., Richel, D. J., & Wilmink, J. W. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00027-3 · Cited by 361
Self-citationJustice, J. N., Ferrucci, L., Newman, A. B., Aroda, V. R., Bahnson, J. L., Divers, J., Espeland, M. A., Marcovina, S., Pollak, M. N., Kritchevsky, S. B., et al. (2018) · GeroScience · doi:10.1007/s11357-018-0042-y · Cited by 359
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Wang, Z., Chen, Z., Jiang, Z., Luo, P., Liu, L., Huang, Y., Wang, H., Wang, Y., Long, L., Tan, X., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10386-8 · Cited by 219
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Zhou, J. Y., Massey, S., Story, D. T., & Li, L. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102863 · Cited by 242
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Jiang, L., Yin, X., Chen, Y., Chen, Y., Jiang, W., Zheng, H., Huang, F., Liu, B., Zhou, W., Qi, L., et al. (2020) · Theranostics · doi:10.7150/thno.43895 · Cited by 217
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Cheng, G., Zielonka, J., Ouari, O., López, M., McAllister, D. M., Boyle, K., Barrios, C. S., Weber, J. J., Johnson, B. D., Hardy, M., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-2534 · Cited by 216
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Gremke, N., Polo, P., Dort, A., Schneikert, J., Elmshäuser, S., Brehm, C. U., Klingmüller, U., Schmitt, A., Reinhardt, H. C., Timofeev, O. N., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18504-7 · Cited by 192
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Masoud, R., Reyes-Castellanos, G., Lac, S., Garcia, J., Dou, S., Shintu, L., Abdel Hadi, N., Gicquel, T., El Kaoutari, A., Diémé, B., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100143 · Cited by 175
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Saini, N., & Yang, X. (2017) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmx106 · Cited by 180
Katila, N., Bhurtel, S., Shadfar, S., Srivastav, S., Neupane, S., Ojha, U., Jeong, G.-S., & Choi, D.-Y. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.08.015 · Cited by 169
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Liang, X., Weng, J., You, Z., Wang, Y., Wen, J., Xia, Z., Huang, S., Luo, P., & Cheng, Q. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02375-x · Cited by 204
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Schöckel, L., Glasauer, A., Basit, F., Bitschar, K., Truong, H., Erdmann, G., Algire, C., Hägebarth, A., Willems, P. H., Kopitz, C., et al. (2015) · Cancer & Metabolism · doi:10.1186/s40170-015-0138-0 · Cited by 161
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Joshi, S., Tolkunov, D., Aviv, H., Hakimi, A. A., Yao, M., Hsieh, J. J.-D., Ganesan, S., Chan, C. S., & White, E. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.059 · Cited by 162
Exercise training response heterogeneity: physiological and molecular insights.
Sparks, L. M. (2017) · Diabetologia · doi:10.1007/s00125-017-4461-6 · Cited by 160
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Xu, Y., Xue, D., Bankhead, A., & Neamati, N. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01013 · Cited by 173
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Liu, J., Zhou, G., Wang, X., & Liu, D. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04490-0 · Cited by 161
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Wang, G. S., & Hoyte, C. O. (2018) · Journal of Intensive Care Medicine · doi:10.1177/0885066618793385 · Cited by 164
Lee, M. (2015) · World Journal of Biological Chemistry · doi:10.4331/wjbc.v6.i3.148 · Cited by 152
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Cameron, A., Logie, L., Patel, K., Erhardt, S., Bacon, S., Middleton, P. K., Harthill, J. E., Forteath, C., Coats, J. T., Kerr, C., et al. (2017) · Redox Biology · doi:10.1016/j.redox.2017.08.018 · Cited by 154
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Urra, F. A., Muñoz, F., Lovy, A., & Cárdenas, C. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00118 · Cited by 149
Baumgart, M., Priebe, S., Groth, M., Hartmann, N., Menzel, U., Pandolfini, L., Koch, P., Felder, M., Ristow, M., Englert, C., et al. (2016) · Cell Systems · doi:10.1016/j.cels.2016.01.014 · Cited by 150
Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer
Nayak, A. P., Kapur, A., Barroilhet, L. M., & Patankar, M. S. (2018) · Cancers · doi:10.3390/cancers10090337 · Cited by 149
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Soberanes, S., Misharin, A. V., Jairaman, A., Morales-Nebreda, L., McQuattie-Pimentel, A. C., Cho, T., Hamanaka, R. B., Meliton, A. Y., Reyfman, P. A., Walter, J. M., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.019 · Cited by 131
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Chen, Y., Fan, Z., Yang, Y., & Gu, C. (2019) · International Journal of Oncology · doi:10.3892/ijo.2019.4720 · Cited by 146
Kim, S. H., Li, M., Trousil, S., Zhang, Y., di Magliano, M. P., Swanson, K. D., & Zheng, B. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.03.033 · Cited by 142
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Gravel, S.-P., Hulea, L., Toban, N., Birman, E., Blouin, M.-J., Zakikhani, M., Zhao, Y., Topisirovic, I., St-Pierre, J., & Pollak, M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-2643-t · Cited by 138
Self-citationIschemic A/D transition of mitochondrial complex I and its role in ROS generation
Dröse, S., Степанова, А., & Galkin, A. S. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.12.013 · Cited by 140
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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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