Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. N. Khan1, M. Auranen1, I. Paetau1, E. Pirinen2, L. Euro1, C. Carroll1, J. Auwerx2, A. Suomalainen1 1) Molecular Neurology, Biomedicum, Helsinki, FI., Finland; 2) Laboratory of Integrative Systems Physiology, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.

   Mitochondrial disorders are the most common group of inherited metabolic diseases. These disorders manifest with respiratory chain deficiency (RCD), but lead to a multitude of clinical manifestations, not explained purely by ATP-deficiency. Despite their progressive and often fatal outcome, no curative treatment is available. Therapy trials have been hampered by the absence of patient groups with homogenous genetic and clinical presentations. Therefore, development of mouse models, replicating the disease phenotype of patients, are essential for understanding the molecular basis of the metabolic consequences of the patients for enabling disease intervention. We have previously generated the mouse model with adult onset mitochondrial myopathy. Molecular data from patients and mice suggested a role for nutrient signaling in the pathogenesis, with disease-induced pseudostarvation response. True fasting increases NAD+:NADH ratio, which activates SIRT1 deacetylase, mitochondrial biogenesis, lipid oxidation and ATP-production. We hypothesized that RCD reduces NADH utilization, decreasing NAD+/NADH and signaling for high nutrient availability, leaving Sirt1 inactive and attenuating mitochondrial biogenesis. However, RCD also decreases ATP production, increasing AMP/ATP, signaling for low nutrition availability, and leading to a potential conflict in nutrient sensor activation and a partial pseudo-starvation response.We report that per-oral nicotinamide riboside (NR), a vitamin-B3-form and NAD+ precursor, boosts NAD+ levels and effectively delayed mouse MM progression. NR robustly induced mitochondrial biogenesis in muscle and brown fat, cured mitochondrial ultrastructure, and decreased mtDNA deletion load -hallmarks of MM. The MM-mice displayed a mitochondrial unfolded protein response (UPRmt), with induction of fasting-cytokine FGF21. NR further enhanced UPRmt, supporting a protective role of UPRmt upon MM. These results indicate that vitamin cofactors modify metabolism and that treatment strategies increasing NAD+ are warranted for MM.

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