Effects of nicotinamide riboside in mitochondrial DNA disease

Background: Mitochondrial disorders are a common cause of inherited neurometabolic disease affecting around 1 in 8000 people. There are currently no treatments for heteroplasmic mitochondrial DNA (mtDNA) disorders which target the underlying disease mechanisms. Increasing nicotinamide adenine dinucleotide (NAD+) with nicotinamide riboside (NR) has been proposed as a therapeutic strategy. It was effective in several models of impaired oxidative metabolism but has not been tested before in humans. Methods: We performed an experimental medicine study in eight participants affected with mtDNA disorders. Three had single large-scale mtDNA deletions and five had m.3243A>G/T pathogenic variants. They were treated with 4-weeks of NR (1250-2000 mg/day). Clinical outcomes (timed up and go test, six-minute walk test, grip strength and quality of life questionnaires), GDF15 and FGF21 blood biomarkers, 31P-magnetic resonance spectroscopy measurement of mitochondrial function in vivo and quadriceps muscle biopsy were performed before and after treatment. Muscle histopathology, mtDNA copy number, heteroplasmy level, citrate synthase and respiratory complex activities were analysed, as well as transcriptomic, proteomic and metabolomic analyses. Results: NR was bioavailable and well tolerated. Overall, NR improved the timed up and go (TUG) test. In three participants with single large-scale deletions, there was a decrease in the percentage of cytochrome c oxidase deficient and ragged-red muscle fibres, an increase in respiratory chain complex I and IV activity, and reduction in mtDNA deletion levels which was not seen in five participants with m.3243A>G/T. Unbiased transcriptomic and integrated multi-omic analysis of all eight participants showed the signature of mitochondrial biogenesis, with SIRT1/PGC-1α activation and increased mitochondrial gene expression, enhanced NAD-related metabolite levels, and coordinated changes in mitochondrial protein abundance. Conclusions: We conclude that NR has potential to be the first small-molecule precision treatment for heteroplasmic mtDNA disorders guided by the specific genetic diagnosis. Trial registration The study was prospectively registered on ClinicalTrials.gov, NCT03432871, Registration date 2018-02-14