ArticleCancer & metabolism2014
Metformin directly acts on mitochondria to alter cellular bioenergetics.
Article in Cancer & metabolism, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 240 papers, 3 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
240 citing papers in PubMed, 3 syntheses or guidelines pooled it, 423 citations in OpenAlex.
- Safety of drug use in patients with a primary mitochondrial disease: An international Delphi-based consensus.Journal of inherited metabolic disease · 2020Guideline
- Comparison of the gamma-Pareto convolution with conventional methods of characterising metformin pharmacokinetics in dogs.Journal of pharmacokinetics and pharmacodynamics · 2020Pooled it
- Serum lactate level and mortality in metformin-associated lactic acidosis requiring renal replacement therapy: a systematic review of case reports and case series.BMC nephrology · 2017Pooled it
- Trial
- Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial.The Laryngoscope · 2017Trial
- 5-Fluorouracil-based chemotherapy disrupts autophagy flux and protein synthesis in cultured myotubes: a role for mTORC1 signaling.American journal of physiology. Cell physiology · 2026Article
- Therapeutics Beyond Delivery: Repurposed Drugs and Biologic Pathways.Current hypertension reports · 2026Review
- Metabolic convergence of diabetes and prostate cancer: from dysglycemia to tumor microenvironment reprogramming.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.bioRxiv : the preprint server for biology · 2026Article
- Metformin Alleviates Stress-Induced Premature Senescence of Vascular Endothelial Cells by Regulating Mitocytosis.International journal of molecular sciences · 2026Article
- Article
- Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.Scientific reports · 2026Article
- Organelle contact sites in cancer cells.Cell death & disease · 2026Review
- Article
- Metformin Improves Cognitive Function in a Rat Model of Global Cerebral Ischemia/Reperfusion Injury Via Inhibiting NF-kb Signaling Pathway and Caspase-1/NLRP3 Inflammasome.Molecular neurobiology · 2026Article
- Recent Advances in Mitochondria-Targeted Nano-Drug Delivery Systems for Cancer Therapy.International journal of nanomedicine · 2026Review
- Alteration of metabolic activity regulates mitochondrial temperature in diagnosis in HepG2 hepatocellular carcinoma cells.Scientific reports · 2025Article
- Glycolytic ATP production enables rapid mammalian cell growth.bioRxiv : the preprint server for biology · 2025Article
- Article
- PEGylated liposomal metformin overcomes pharmacokinetic barriers to trigger potent mitochondrial disruption and cell cycle arrest in hepatocellular carcinoma.Scientific reports · 2025Article
180 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMetformin is widely used in the treatment of diabetes, and there is interest in 'repurposing' the drug for cancer prevention or treatment. However, the mechanism underlying the metabolic effects of metformin remains poorly understood.
methodsWe performed respirometry and stable isotope tracer analyses on cells and isolated mitochondria to investigate the impact of metformin on mitochondrial functions.
resultsWe show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells treated with metformin become energetically inefficient, and display increased aerobic glycolysis and reduced glucose metabolism through the citric acid cycle. Conflicting prior studies proposed mitochondrial complex I or various cytosolic targets for metformin action, but we show that the compound limits respiration and citric acid cycle activity in isolated mitochondria, indicating that at least for these effects, the mitochondrion is the primary target. Finally, we demonstrate that cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis than nontransformed cells, highlighting their metabolic vulnerability. Prevention of this compensatory metabolic event in cancer cells significantly impairs survival.
conclusionsTogether, these results demonstrate that metformin directly acts on mitochondria to limit respiration and that the sensitivity of cells to metformin is dependent on their ability to cope with energetic stress.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.