nicotinamide-beta-riboside and Mitochondrial-Diseases

Topics: Adenosine Triphosphate; Alzheimer Disease; Amyloid beta-Peptides; Brain-Derived Neurotrophic Factor; Disease Progression; Exercise; Forkhead Box Protein O1; Humans; Mitochondria; Mitochondrial Diseases; Mitophagy; NAD; Niacinamide; Nicotinamide Mononucleotide; Protein Kinases; Pyridinium Compounds; Reactive Oxygen Species; Sirtuin 1; Ubiquitin-Protein Ligases

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.

Topics: Animals; Dietary Supplements; Disease Models, Animal; Electron Transport Complex IV; Energy Metabolism; Enzyme Activation; Gene Expression; Mice; Mice, Knockout; Mitochondria; Mitochondrial Diseases; Molecular Chaperones; NAD; Niacinamide; Oxidative Phosphorylation; Phenanthrenes; Phenotype; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Pyridinium Compounds; Sirtuin 1