NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease.

TitleNAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease.
Publication TypeJournal Article
Year of Publication2014
AuthorsCerutti, R, Pirinen, E, Lamperti, C, Marchet, S, Sauve, AA, Li, W, Leoni, V, Schon, EA, Dantzer, F, Auwerx, J, Viscomi, C, Zeviani, M
JournalCell Metab
Date Published2014 Jun 03
KeywordsAnimals, Dietary Supplements, Disease Models, Animal, Electron Transport Complex IV, Energy Metabolism, Enzyme Activation, Gene Expression, Mice, Mice, Knockout, Mitochondria, Mitochondrial Diseases, NAD, Niacinamide, Oxidative Phosphorylation, Phenanthrenes, Phenotype, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Sirtuin 1

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.

Alternate JournalCell Metab.
Citation Key10.1016/j.cmet.2014.04.001
PubMed ID24814483
PubMed Central IDPMC4051987
Grant ListMC_UP_1002/1 / / Medical Research Council / United Kingdom
R01 AG043930 / AG / NIA NIH HHS / United States
R01 HL106511 / HL / NHLBI NIH HHS / United States
R01 GM106072 / GM / NIGMS NIH HHS / United States
R01HL106511-01A / HL / NHLBI NIH HHS / United States
R01AG043930 / AG / NIA NIH HHS / United States
P01 HD032062 / HD / NICHD NIH HHS / United States
GPP10005 / / Telethon / Italy