title: Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling.
abstract: Mitochondrial respiratory chain (RC) disorders are the most prevalent inborn metabolic diseases and remain without effective treatment to date. Up-regulation of residual enzyme activity has been proposed as a possible therapeutic approach in this group of disorders. As resveratrol (RSV), a natural compound, was proposed to stimulate mitochondrial metabolism in rodents, we tested the effect of this compound on mitochondrial functions in control or in Complex I (CI)- or Complex IV (CIV)-deficient patients' fibroblasts. We show that RSV stimulates the expression of a panel of proteins representing structural subunits or assembly factors of the five RC complexes, in control fibroblasts. In moderate RC-deficient patients' cells, RSV treatment increases the amount of mutated proteins and stimulates residual enzyme activities. In these patients' cells, we establish that up-regulation of RC enzyme activities induced by RSV translates into increased cellular O2 consumption rates and results in the correction of RC deficiencies. Importantly, RSV also prevents the accumulation of lactate that occurred in RC-deficient fibroblasts. Different complementary approaches demonstrate that RSV induces a mitochondrial biogenesis that might underlie the increase in mitochondrial capacities. Finally, we showed that, in human fibroblasts, RSV stimulated mitochondrial functions mainly in a SIRT1- and AMPK-independent manner and that its effects rather involved the estrogen receptor (ER) and estrogen-related receptor alpha (ERRα) signaling pathways. These results represent the first demonstration that RSV could have a beneficial effect on inborn CI and CIV deficiencies from nuclear origin, in human fibroblasts and might be clinically relevant for the treatment of some RC deficiencies.
authors.affiliation: INSERM U747, Université Paris Descartes, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lopes Costa
authors.forename: Carole
authors.initials: C
authors.lastname: Le Bachelier
authors.forename: Lise
authors.initials: L
authors.lastname: Mathieu
authors.forename: Agnès
authors.initials: A
authors.lastname: Rotig
authors.forename: Avihu
authors.initials: A
authors.lastname: Boneh
authors.forename: Pascale
authors.initials: P
authors.lastname: De Lonlay
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.forename: Jean
authors.initials: J
authors.lastname: Bastin
authors.forename: Fatima
authors.initials: F
authors.lastname: Djouadi
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D030401:Cytochrome-c Oxidase Deficiency / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004579:Electron Transport / Q000187:drug effects; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007773:Lactates; D051336:Mitochondrial Membranes / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011773:Pyruvates; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013267:Stilbenes / Q000494:pharmacology*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D016588:Anticarcinogenic Agents; D042967:Electron Transport Complex I; D003576:Electron Transport Complex IV; D047628:Estrogen Receptor alpha; D007773:Lactates; D011773:Pyruvates; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D000077185:Resveratrol; D056564:Sirtuin 1; D013267:Stilbenes; D000097983:ERRalpha Estrogen-Related Receptor; C506487:ESR1 protein, human; C447939:SIRT1 protein, human