Hepatocyte mitochondrial NAD⁺ content is limiting for liver regeneration

Nicotinamide adenine dinucleotide (NAD⁺) precursor supplementation shows metabolic and functional benefits in rodent models of disease and is being explored as potential therapeutic strategy in humans. However, the wide range of processes that involve NAD⁺ in every cell and subcellular compartment make it difficult to narrow down the mechanisms of action. Here we show that the rate of liver regeneration is closely associated with the concentration of NAD⁺ in hepatocyte mitochondria. We find that the mitochondrial NAD⁺ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1). The heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD⁺ content in multiple tissues and impairs liver regeneration, whereas the hepatocyte-specific overexpression of SLC25A51 is sufficient to enhance liver regeneration comparably to the effect of systemic NAD⁺ precursor supplements. This benefit is observed even though NAD⁺ levels are increased only in mitochondria. Thus, the hepatocyte mitochondrial NAD⁺ pool is a key determinant of the rate of liver regeneration.