NAD+ precursor treatment prevents cardiomyopathybut disrupts erythroid maturation in mitochondrial progeria

Nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, and its decline is linked to various degenerative diseases. While NAD+ restoration holds therapeutic promise, its long term, tissue-specific consequences remain poorly understood. We investigated effects of nicotinamide riboside (NR) supplementation for "mutator" mice manifesting mitochondrial progeria. Our results reveal strikingly divergent outcomes: in proliferative bone marrow, NR-treated mutators show reductive stress with accumulation of NADH/NADPH, altered amino acid, nucleotide, folate levels and impaired heme biosynthesis. In blood, erythrocyte maturation defects are aggravated, exacerbating anemia. Conversely, in postmitotic cardiac tissue, NR enhanced contractility, reduces stress response markers and normalized metabolic profile. These findings indicate that while being beneficial for heart, chronic NAD+ boosting can compromise erythrocyte maturation in the context of mitochondrial disease. The data emphasize importance of evaluating systemic effects of NAD+ boosting therapies beyond the primary affected tissues and development of tissue-specific metabolic interventions for degenerative diseases. HighlightsO_LIChronic nicotinamide riboside supplementation exacerbates anemia and disrupts erythroid maturation in progeric mice. C_LIO_LIIn proliferative bone marrow cells, NR induces redox imbalance and drives profound metabolic dysregulation. C_LIO_LINR suppresses heme biosynthesis and iron transport pathways in the bone marrow. C_LIO_LIIn the heart, NR restores NAD+ levels, enhances cardiac function, and reduces metabolic stress. C_LI