ArticleScience (New York, N.Y.)2023
Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides.
Article in Science (New York, N.Y.), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 121 citations in OpenAlex.
- Direct Pharmacological Activation of AMPK Extends Lifespan in Yeast, Worms and Flies.Aging cell · 2026Article
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- Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.Nature metabolism · 2026Article
- Article
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- Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.Nature communications · 2026Article
- Repression of EGFR by new biguanide 4C potentiated ovarian cancer to PARP inhibitors through down-regulation of BRCA2 and Rad51.Cell death & disease · 2026Article
- Metformin induces ferroptosis associated with lipidomic remodeling in AML.Blood advances · 2026Article
- Beyond exercise and appetite: The expanding biology and therapeutic potential of N-lactoyl-phenylalanine.The Journal of pharmacology and experimental therapeutics · 2026Review
- Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.Nature communications · 2026Article
- Hydrophilic metformin and hydrophobic biguanides inhibit mitochondrial complex I by distinct mechanisms.Nature structural & molecular biology · 2026Article
- Meta-analysis of functional genomics studies reveals conserved cellular pathways required by viruses of pandemic concern.Access microbiology · 2026Article
- Mammalian Respiratory Chain Complex Assemblies and Their Links to Mitochondria Stress-Induced Human Diseases.Advances in experimental medicine and biology · 2026Review
- Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.Cell death and differentiation · 2025Article
- An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.International journal of molecular sciences · 2025Article
- Cryo-EM single-particle analysis expanding towards increasingly native samples.Acta crystallographica. Section D, Structural biology · 2025Review
- Target practice: Opportunities for therapeutic intervention in CHIP and CCUS.Blood reviews · 2025Review
- Novel combination therapy with phenformin enhances the effects of lenvatinib in hepatocellular carcinoma via AMPK-mediated PDGFRβ degradation.Cancer cell international · 2025Article
- Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycemic control.bioRxiv : the preprint server for biology · 2025Article
- Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.Nature aging · 2025Article
14 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We interpret these data to explain the selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel, and an additional binding site is in a pocket on the intermembrane-space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable the rational design of medicinal biguanides.
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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.