The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin.
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.
Batandier
Cécile
C
INSERM E-0221 Bioénergétique Fondamentale et Appliquée, Universit Joseph Fourier, Grenoble, F-38000, France.
Guigas
Bruno
B
Detaille
Dominique
D
El-Mir
M-Yehia
MY
Fontaine
Eric
E
Rigoulet
M
M
Leverve
Xavier M
XM
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
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