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

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

Author information

1
Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, 20133 Milan, Italy; MRC-Mitochondrial Biology Unit, Cambridge CB2 0XY, UK.
2
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.
3
Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, 20133 Milan, Italy.
4
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA.
5
Laboratory of Clinical Pathology and Medical Genetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, 20133 Milan, Italy.
6
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
7
Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, 67412 Illkirch, France.
8
Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
9
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.
10
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.

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.

PMID:
24814483
PMCID:
PMC4051987
DOI:
10.1016/j.cmet.2014.04.001
[Indexed for MEDLINE]
Free PMC Article

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