1. An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals
- Author
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Detaille, Dominique, Pasdois, Philippe, Sémont, Audrey, Santos, Pierre, Diolez, Philippe, Institut de rythmologie et modélisation cardiaque [Pessac] (IHU Liryc), Université de Bordeaux (UB), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], This work was supported by the Centre National de la Recherche Scientifique (P.D. salary), the French Government as part of the ‘investments for the future’ program managed by the National Research Agency (ANR), Grant reference ANR-10-IAHU-04, and the grant MITOCARD ANR-17-CE11-0041 (P.D.). The authors thanks the company OP2drugs (Pessac, France) for providing the anethol trithione (OP2113) compound., ANR-10-IAHU-0004,LIRYC,L'Institut de Rythmologie et modélisation Cardiaque(2010), ANR-17-CE11-0041,MITOCARD,Electrophysiologie de la Mitochondrie Cardiaque(2017), Bodescot, Myriam, Instituts Hospitalo-Universitaires - L'Institut de Rythmologie et modélisation Cardiaque - - LIRYC2010 - ANR-10-IAHU-0004 - IAHU - VALID, and Electrophysiologie de la Mitochondrie Cardiaque - - MITOCARD2017 - ANR-17-CE11-0041 - AAPG2017 - VALID
- Subjects
Male ,Metabolic Processes ,Critical Care and Emergency Medicine ,Science ,Myocardial Infarction ,Cardiology ,Bioenergetics ,Biochemistry ,Vascular Medicine ,Mitochondria, Heart ,Oxidative Phosphorylation ,Antioxidants ,Ischemia ,Heart Rate ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Medicine and Health Sciences ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Rats, Wistar ,Energy-Producing Organelles ,Electron Transport Complex I ,Biology and Life Sciences ,Heart ,Neurochemistry ,Free Radical Scavengers ,Cell Biology ,Neurotransmitters ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,Myocardial Contraction ,Rats ,Mitochondria ,[SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences ,Disease Models, Animal ,Metabolism ,Reperfusion ,Cardiovascular Anatomy ,Medicine ,Cellular Structures and Organelles ,Anatomy ,Glutamate ,Reactive Oxygen Species ,Research Article ,Neuroscience - Abstract
International audience; FINDINGS: Here, we demonstrate that OP2113 (5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione, CAS 532-11-6), synthesized and used as a drug since 1696, does not act as an unspecific antioxidant molecule (i.e., as a radical scavenger) but unexpectedly decreases mitochondrial reactive oxygen species (ROS/H2O2) production by acting as a specific inhibitor of ROS production at the IQ site of complex I of the mitochondrial respiratory chain. Studies performed on isolated rat heart mitochondria also showed that OP2113 does not affect oxidative phosphorylation driven by complex I or complex II substrates. We assessed the effect of OP2113 on an infarct model of ex vivo rat heart in which mitochondrial ROS production is highly involved and showed that OP2113 protects heart tissue as well as the recovery of heart contractile activity.CONCLUSION / SIGNIFICANCE: This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H2O2. OP2113 therefore appears to be a member of the new class of mitochondrial ROS blockers (S1QELs) and could protect mitochondrial function in numerous diseases in which ROS-induced mitochondrial dysfunction occurs. These applications include but are not limited to aging, Parkinson's and Alzheimer's diseases, cardiac atrial fibrillation, and ischemia-reperfusion injury.
- Published
- 2018
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