title: Resveratrol Directly Binds to Mitochondrial Complex I and Increases Oxidative Stress in Brain Mitochondria of Aged Mice.
abstract: Resveratrol is often described as a promising therapeutic molecule for numerous diseases, especially in metabolic and neurodegenerative disorders. While the mechanism of action is still debated, an increasing literature reports that resveratrol regulates the mitochondrial respiratory chain function. In a recent study we have identified mitochondrial complex I as a direct target of this molecule. Nevertheless, the mechanisms and consequences of such an interaction still require further investigation. In this study, we identified in silico by docking study a binding site for resveratrol at the nucleotide pocket of complex I. In vitro, using solubilized complex I, we demonstrated a competition between NAD+ and resveratrol. At low doses (<5μM), resveratrol stimulated complex I activity, whereas at high dose (50 μM) it rather decreased it. In vivo, in brain mitochondria from resveratrol treated young mice, we showed that complex I activity was increased, whereas the respiration rate was not improved. Moreover, in old mice with low antioxidant defenses, we demonstrated that complex I activation by resveratrol led to oxidative stress. These results bring new insights into the mechanism of action of resveratrol on mitochondria and highlight the importance of the balance between pro- and antioxidant effects of resveratrol depending on its dose and age. These parameters should be taken into account when clinical trials using resveratrol or analogues have to be designed.
authors.affiliation: Université d'Angers, Angers, F-49000, France.|Département de Biochimie et Génétique, CHU d'Angers, Angers, F-49000, France.|UMR CNRS 6214-INSERM U1083, Angers, F-49000, France.
authors.forename: Naïg
authors.initials: N
authors.lastname: Gueguen
authors.affiliation: Université d'Angers, Angers, F-49000, France.|Département de Biochimie et Génétique, CHU d'Angers, Angers, F-49000, France.|UMR CNRS 6214-INSERM U1083, Angers, F-49000, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Desquiret-Dumas
authors.affiliation: Université d'Angers, Angers, F-49000, France.|UMR CNRS 6214-INSERM U1083, Angers, F-49000, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Leman
authors.affiliation: Université d'Angers, Angers, F-49000, France.|Département de Biochimie et Génétique, CHU d'Angers, Angers, F-49000, France.|UMR CNRS 6214-INSERM U1083, Angers, F-49000, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Chupin
authors.affiliation: EA 4466, Université Paris Descartes, Faculté de Pharmacie, Paris, F-75270, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baron
authors.affiliation: EA 4466, Université Paris Descartes, Faculté de Pharmacie, Paris, F-75270, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Nivet-Antoine
authors.affiliation: Université d'Angers, Angers, F-49000, France.|UMR CNRS 6214-INSERM U1083, Angers, F-49000, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Vessières
authors.affiliation: Université d'Angers, Angers, F-49000, France.|UMR CNRS 6214-INSERM U1083, Angers, F-49000, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Ayer
authors.affiliation: Université d'Angers, Angers, F-49000, France.|UMR CNRS 6214-INSERM U1083, Angers, F-49000, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.affiliation: Université d'Angers, Angers, F-49000, France.|UMR CNRS 6214-INSERM U1083, Angers, F-49000, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.affiliation: Université d'Angers, Angers, F-49000, France.|Département de Biochimie et Génétique, CHU d'Angers, Angers, F-49000, France.|UMR CNRS 6214-INSERM U1083, Angers, F-49000, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.affiliation: Université d'Angers, Angers, F-49000, France.|Département de Biochimie et Génétique, CHU d'Angers, Angers, F-49000, France.|UMR CNRS 6214-INSERM U1083, Angers, F-49000, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
mesh_terms: D000367:Age Factors; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000737:chemistry* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D013267:Stilbenes; D009243:NAD; D042967:Electron Transport Complex I; D000077185:Resveratrol