title: NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease.
abstract: Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD(+)-dependent protein deacetylase. As NAD(+) boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD(+) play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD(+) precursor, or reduction of NAD(+) consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans.
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, 20133 Milan, Italy; MRC-Mitochondrial Biology Unit, Cambridge CB2 0XY, UK.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Cerutti
authors.affiliation: Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland; Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, FI-70211 Kuopio, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Pirinen
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, 20133 Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, 20133 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marchet
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Sauve
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Laboratory of Clinical Pathology and Medical Genetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, 20133 Milan, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Leoni
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, 67412 Illkirch, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Dantzer
authors.affiliation: Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, 20133 Milan, Italy; MRC-Mitochondrial Biology Unit, Cambridge CB2 0XY, UK. Electronic address: cfv23@mrc-mbu.cam.ac.uk.
authors.forename: Carlo
authors.initials: C
authors.lastname: Viscomi
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, 20133 Milan, Italy; MRC-Mitochondrial Biology Unit, Cambridge CB2 0XY, UK. Electronic address: mdz21@mrc-mbu.cam.ac.uk.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D000818:Animals; D019587:Dietary Supplements; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics; D004734:Energy Metabolism / Q000502:physiology*; D004789:Enzyme Activation; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology; D028361:Mitochondrial Diseases / Q000188:drug therapy; D018832:Molecular Chaperones; D009243:NAD / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010085:Oxidative Phosphorylation; D010616:Phenanthrenes / Q000494:pharmacology; D010641:Phenotype; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D011726:Pyridinium Compounds; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011726:Pyridinium Compounds; C511423:SCO2 protein, mouse; C018613:nicotinamide-beta-riboside; D009243:NAD; D009536:Niacinamide; D003576:Electron Transport Complex IV; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1