NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells

Nat Commun. 2016 Oct 11;7:13103. doi: 10.1038/ncomms13103.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Hep G2 Cells
  • Hepatocytes / metabolism
  • Humans
  • Injections, Intraperitoneal
  • Mammals / metabolism*
  • Mice, Knockout
  • NAD / biosynthesis
  • Niacinamide / analogs & derivatives*
  • Niacinamide / metabolism
  • Nicotinamide Mononucleotide / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*

Substances

  • nicotinamide-beta-riboside
  • NAD
  • Nicotinamide Mononucleotide
  • Niacinamide
  • Phosphotransferases (Alcohol Group Acceptor)
  • NMRK1 protein, human
  • Nmrk1 protein, mouse