title: The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin.
abstract: Mitochondrial reactive oxygen species (ROS) production was investigated in mitochondria extracted from liver of rats treated with or without metformin, a mild inhibitor of respiratory chain complex 1 used in type 2 diabetes. A high rate of ROS production, fully suppressed by rotenone, was evidenced in non-phosphorylating mitochondria in the presence of succinate as a single complex 2 substrate. This ROS production was substantially lowered by metformin pretreatment and by any decrease in membrane potential (Delta Phi(m)), redox potential (NADH/NAD), or phosphate potential, as induced by malonate, 2,4-dinitrophenol, or ATP synthesis, respectively. ROS production in the presence of glutamate-malate plus succinate was lower than in the presence of succinate alone, but higher than in the presence of glutamate-malate. Moreover, while rotenone both increased and decreased ROS production at complex 1 depending on forward (glutamate-malate) or reverse (succinate) electron flux, no ROS overproduction was evidenced in the forward direction with metformin. Therefore, we propose that reverse electron flux through complex 1 is an alternative pathway, which leads to a specific metformin-sensitive ROS production.
authors.affiliation: INSERM E-0221 Bioénergétique Fondamentale et Appliquée, Universit Joseph Fourier, Grenoble, F-38000, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Batandier
authors.forename: Bruno
authors.initials: B
authors.lastname: Guigas
authors.forename: Dominique
authors.initials: D
authors.lastname: Detaille
authors.forename: M-Yehia
authors.initials: MY
authors.lastname: El-Mir
authors.forename: Eric
authors.initials: E
authors.lastname: Fontaine
authors.forename: M
authors.initials: M
authors.lastname: Rigoulet
authors.forename: Xavier M
authors.initials: XM
authors.lastname: Leverve
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000502:physiology*; D018698:Glutamic Acid / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008293:Malates / Q000494:pharmacology; D008314:Malonates / Q000494:pharmacology; D008564:Membrane Potentials; D008687:Metformin / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D019802:Succinic Acid / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D008293:Malates; D008314:Malonates; D017382:Reactive Oxygen Species; D012402:Rotenone; D018698:Glutamic Acid; C030298:malic acid; D000255:Adenosine Triphosphate; D008687:Metformin; C030290:malonic acid; D019802:Succinic Acid; D042967:Electron Transport Complex I; D019297:2,4-Dinitrophenol