Our data suggested that normalizing NADH:NAD+ ratio with NR may be a potential treatment for glycolytic and fatty acid β-oxidation defects in citrin deficiency in the liver. Additionally, increasing cytoplasmic NAD+ levels may be useful for the treatment of other monogenic mitochondrial diseases involving the aspartate malate shuttle and mitochondrial transporters...Our findings suggest that correcting the cytoplasmic NADH:NAD+ ratio may be a useful strategy to treat some of the metabolic dysfunction in genetic mitochondrial diseases.