The ROS Production Induced by a Reverse-Electron Flux at Respiratory-Chain Complex 1 is Hampered by Metformin |
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Authors: | Cécile Batandier Bruno Guigas Dominique Detaille M El-Mir Eric Fontaine M Rigoulet X M Leverve |
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Institution: | (1) INSERM E-0221 Bioénergétique Fondamentale et Appliquée, Universit Joseph Fourier, Grenoble, F-38000, France;(2) Faculty of Pharmacy, Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain;(3) Institut de Biochimie et de Génétique Cellulaire de CNRS, Universit de Bordeaux II, 33077 Bordeaux Cedex, France;(4) Bioénergétique Fondamentale et Appliquée INSERM E-0221, Universit Joseph Fourier, BP 53X, 38041 Grenoble Cedex, France |
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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 (Δ < eqid1 > 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. |
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Keywords: | Metformin ROS Oxidative phosphorylation Rat liver mitochondria Rotenone Malonate Antimycin Membrane potential |
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