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

Cell Metab. 2014 Jun 3;19(6):1042-9. doi: 10.1016/j.cmet.2014.04.001. Epub 2014 May 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dietary Supplements
  • Disease Models, Animal
  • Electron Transport Complex IV / biosynthesis
  • Electron Transport Complex IV / genetics
  • Energy Metabolism / physiology*
  • Enzyme Activation
  • Gene Expression
  • Mice
  • Mice, Knockout
  • Mitochondria / pathology
  • Mitochondrial Diseases / drug therapy
  • Molecular Chaperones
  • NAD / metabolism*
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Oxidative Phosphorylation
  • Phenanthrenes / pharmacology
  • Phenotype
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / genetics
  • Sirtuin 1 / metabolism*

Substances

  • Molecular Chaperones
  • N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
  • Phenanthrenes
  • Poly(ADP-ribose) Polymerase Inhibitors
  • SCO2 protein, mouse
  • nicotinamide-beta-riboside
  • NAD
  • Niacinamide
  • Electron Transport Complex IV
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Sirt1 protein, mouse
  • Sirtuin 1