title: Resveratrol induces a mitochondrial complex I-dependent increase in NADH oxidation responsible for sirtuin activation in liver cells.
abstract: Resveratrol (RSV) has been shown to be involved in the regulation of energetic metabolism, generating increasing interest in therapeutic use. SIRT1 has been described as the main target of RSV. However, recent reports have challenged the hypothesis of its direct activation by RSV, and the signaling pathways remain elusive. Here, the effects of RSV on mitochondrial metabolism are detailed both in vivo and in vitro using murine and cellular models and isolated enzymes. We demonstrate that low RSV doses (1-5 μM) directly stimulate NADH dehydrogenases and, more specifically, mitochondrial complex I activity (EC50 ∼1 μM). In HepG2 cells, this complex I activation increases the mitochondrial NAD(+)/NADH ratio. This higher NAD(+) level initiates a SIRT3-dependent increase in the mitochondrial substrate supply pathways (i.e. the tricarboxylic acid cycle and fatty acid oxidation). This effect is also seen in liver mitochondria of RSV-fed animals (50 mg/kg/day). We conclude that the increase in NADH oxidation by complex I is a crucial event for SIRT3 activation by RSV. Our results open up new perspectives in the understanding of the RSV signaling pathway and highlight the critical importance of RSV doses used for future clinical trials.
authors.affiliation: From Angers Université, Angers F-49000, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Desquiret-Dumas
authors.forename: Naïg
authors.initials: N
authors.lastname: Gueguen
authors.forename: Géraldine
authors.initials: G
authors.lastname: Leman
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baron
authors.forename: Valérie
authors.initials: V
authors.lastname: Nivet-Antoine
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Chupin
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chevrollier
authors.forename: Emilie
authors.initials: E
authors.lastname: Vessières
authors.forename: Audrey
authors.initials: A
authors.lastname: Ayer
authors.forename: Marc
authors.initials: M
authors.lastname: Ferré
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
mesh_terms: D000818:Animals; D042967:Electron Transport Complex I / Q000378:metabolism*; D004789:Enzyme Activation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D010084:Oxidation-Reduction; D000077185:Resveratrol; D056566:Sirtuin 3 / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: C525046:Sirt3 protein, mouse; D013267:Stilbenes; D009243:NAD; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D042967:Electron Transport Complex I; D000077185:Resveratrol
keywords: Complex I; Mitochondria; Mitochondrial Metabolism; NAD; NADH Dehydrogenase; Resveratrol; Sirtuins