ArticleBiochemistry2015
Selective inhibition of deactivated mitochondrial complex I by biguanides.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 79 citations in OpenAlex.
- Article
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- Energy Metabolism and Metformin: Effects on Ischemia-Reperfusion Injury in Kidney Transplantation.Biomedicines · 2024Review
- Preneoplastic cells switch to Warburg metabolism from their inception exposing multiple vulnerabilities for targeted elimination.Oncogenesis · 2024Article
- All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.Nature communications · 2023Article
- Preventing mitochondrial reverse electron transport as a strategy for cardioprotection.Basic research in cardiology · 2023Review
- First-in-Class NADH/Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) Antagonist for the Treatment of Pancreatic Cancer.ACS pharmacology & translational science · 2023Article
- A New Quinone-Based Inhibitor of Mitochondrial Complex I in D-Conformation, Producing Invasion Reduction and Sensitization to Venetoclax in Breast Cancer Cells.Antioxidants (Basel, Switzerland) · 2023Article
- Administration of metformin rescues age-related vulnerability to ischemic insults through mitochondrial energy metabolism.Biochemical and biophysical research communications · 2023Article
- Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides.Science (New York, N.Y.) · 2023Article
- Loss of Myostatin Alters Mitochondrial Oxidative Phosphorylation, TCA Cycle Activity, and ATP Production in Skeletal Muscle.International journal of molecular sciences · 2022Article
- Effect of metformin on intact mitochondria from liver and brain: Concept revisited.European journal of pharmacology · 2022Article
- Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts.Cancers · 2022Article
- Structure of respiratory complex I - An emerging blueprint for the mechanism.Current opinion in structural biology · 2022Review
- Therapeutic Targets for Regulating Oxidative Damage Induced by Ischemia-Reperfusion Injury: A Study from a Pharmacological Perspective.Oxidative medicine and cellular longevity · 2022Review
- Effects of Metformin on Spontaneous CaInternational journal of molecular sciences · 2021Article
- Biphasic effect of metformin on human cardiac energetics.Translational research : the journal of laboratory and clinical medicine · 2021Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Biguanides are widely used antihyperglycemic agents for diabetes mellitus and prediabetes treatment. Complex I is the rate-limiting step of the mitochondrial electron transport chain (ETC), a major source of mitochondrial free radical production, and a known target of biguanides. Complex I has two reversible conformational states, active and de-active. The deactivated state is promoted in the absence of substrates but is rapidly and fully reversed to the active state in the presence of NADH. The objective of this study was to determine the relative sensitivity of active/de-active complex I to biguanide-mediated inhibition and resulting superoxide radical (O₂(•⁻)) production. Using isolated rat heart mitochondria, we show that deactivation of complex I sensitizes it to metformin and phenformin (4- and 3-fold, respectively), but not to other known complex I inhibitors, such as rotenone. Mitochondrial O₂(•⁻) production by deactivated complex I was measured fluorescently by NADH-dependent 2-hydroxyethidium formation at alkaline pH to impede reactivation. Superoxide production was 260.4% higher than in active complex I at pH 9.4. However, phenformin treatment of de-active complex I decreased O₂(•⁻) production by 14.9%, while rotenone increased production by 42.9%. Mitochondria isolated from rat hearts subjected to cardiac ischemia, a condition known to induce complex I deactivation, were sensitized to phenformin-mediated complex I inhibition. This supports the idea that the effects of biguanides are likely to be influenced by the complex I state in vivo. These results demonstrate that the complex I active and de-active states are a determinant in biguanide-mediated inhibition.
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Registered trials
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