title: Resveratrol attenuates oxidative stress in mitochondrial Complex I deficiency: Involvement of SIRT3.
abstract: The pathophysiological mechanisms underlying Complex I (CI) deficiencies are understood only partially which severely limits the treatment of this common, devastating, mitochondrial disorder. Recently, we have shown that resveratrol (RSV), a natural polyphenol, has beneficial effects on CI deficiency of nuclear origin. Here, we demonstrate that RSV is able to correct the biochemical defect in oxygen consumption in five of thirteen CI-deficient patient cell lines. Other beneficial effects of RSV include a decrease of total intracellular ROS and the up-regulation of the expression of mitochondrial superoxide dismutase (SOD2) protein, a key antioxidant defense enzyme. The molecular mechanisms leading to the up-regulation of SOD2 protein expression by RSV require the estrogen receptor (ER) and the estrogen-related receptor alpha (ERRα). Although RSV increases the level of SOD2 protein in patients' fibroblasts, the enzyme activity is not increased, in contrast to normal fibroblasts. This led us to hypothesize that SOD2 enzyme activity is regulated post-translationally. This regulation involves SIRT3, a mitochondrial NAD(+)-dependent deacetylase and is critically dependent on NAD(+) levels. Taken together, our data show that the metabolic effects of RSV combined with its antioxidant capacities makes RSV particularly interesting as a candidate molecule for the therapy of CI deficiencies.
authors.affiliation: INSERM UMRS 1124, Université Paris Descartes, 75006 Paris, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Mathieu
authors.affiliation: INSERM UMRS 1124, Université Paris Descartes, 75006 Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lopes Costa
authors.affiliation: INSERM UMRS 1124, Université Paris Descartes, 75006 Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Le Bachelier
authors.affiliation: Laboratoire de Biochimie, AP-HP Hôpital, 94270 Kremlin Bicêtre, France.
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Slama
authors.affiliation: CHU Reims, Hôpital Maison Blanche, Pôle de Biologie, Service de Génétique, 51092 Reims, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Lebre
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: INSERM UMRS 1124, Université Paris Descartes, 75006 Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Bastin
authors.affiliation: INSERM UMRS 1124, Université Paris Descartes, 75006 Paris, France. Electronic address: fatima.djouadi@inserm.fr.
authors.forename: Fatima
authors.initials: F
authors.lastname: Djouadi
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010101:Oxygen Consumption / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056566:Sirtuin 3 / Q000235:genetics*; D013267:Stilbenes / Q000008:administration & dosage*; D013482:Superoxide Dismutase / Q000235:genetics*; D000097983:ERRalpha Estrogen-Related Receptor; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D042967:Electron Transport Complex I; D047628:Estrogen Receptor alpha; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D000077185:Resveratrol; D056566:Sirtuin 3; D013267:Stilbenes; D013482:Superoxide Dismutase; D000097983:ERRalpha Estrogen-Related Receptor; D000099156:Superoxide Dismutase 2; C506487:ESR1 protein, human; C466093:SIRT3 protein, human
keywords: Complex I deficiency; Mitochondrial diseases; Oxidative stress; Pharmacological therapy; Resveratrol; SIRT3; SOD2