NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells

NAD(+) is a vital redox cofactor and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Supplementation with NAD(+) precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), protects against metabolic disease, neurodegenerative disorders and age-related physiological decline in mammals. Here we show that nicotinamide riboside kinase 1 (NRK1) is necessary and rate-limiting for the use of exogenous NR and NMN for NAD(+) synthesis. Using genetic gain- and loss-of-function models, we further demonstrate that the role of NRK1 in driving NAD(+) synthesis from other NAD(+) precursors, such as nicotinamide or nicotinic acid, is dispensable. Using stable isotope-labelled compounds, we confirm NMN is metabolized extracellularly to NR that is then taken up by the cell and converted into NAD(+). Our results indicate that mammalian cells require conversion of extracellular NMN to NR for cellular uptake and NAD(+) synthesis, explaining the overlapping metabolic effects observed with the two compounds.