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: Raffaele Cerutti, Eija Pirinen, Costanza Lamperti, Silvia Marchet, Anthony A Sauve, Wei Li, Valerio Leoni, Eric A Schon, Françoise Dantzer, Johan Auwerx, Carlo Viscomi, Massimo Zeviani
• Journal: Cell metabolism (Cell Metab) Vol. 19 Issue 6 Pg. 1042-9 (Jun 03 2014) ISSN: 1932-7420 [Electronic] United States
• PMID: 24814483 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Molecular Chaperones
• N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
• Phenanthrenes
• Poly(ADP-ribose) Polymerase Inhibitors
• Pyridinium Compounds
• 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

Topics

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