title: NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells.
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.
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Lausanne CH-1015, Switzerland.|School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Ratajczak
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Lausanne CH-1015, Switzerland.
authors.forename: Magali
authors.initials: M
authors.lastname: Joffraud
authors.affiliation: Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Samuel A J
authors.initials: SA
authors.lastname: Trammell
authors.affiliation: Group of Research on Omic Methodologies (GROM), Universitat Rovira i Virgili, Reus 43204, Spain.|Centre for Omic Sciences, Universitat Rovira i Virgili, Reus 43204, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Ras
authors.affiliation: Group of Research on Omic Methodologies (GROM), Universitat Rovira i Virgili, Reus 43204, Spain.|Centre for Omic Sciences, Universitat Rovira i Virgili, Reus 43204, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Canela
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Lausanne CH-1015, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Boutant
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Lausanne CH-1015, Switzerland.
authors.forename: Sameer S
authors.initials: SS
authors.lastname: Kulkarni
authors.affiliation: Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.|School of Pharmacy, Queen's University Belfast, Belfast BT7 1NN, UK.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Rodrigues
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast BT7 1NN, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Redpath
authors.affiliation: Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.|School of Pharmacy, Queen's University Belfast, Belfast BT7 1NN, UK.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Migaud
authors.affiliation: Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Centre for Omic Sciences, Universitat Rovira i Virgili, Reus 43204, Spain.|Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid 28029, Spain.|Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona 43007, Spain.
authors.forename: Oscar
authors.identifier: 0000-0003-3695-7157
authors.initials: O
authors.lastname: Yanes
authors.affiliation: Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Charles
authors.identifier: 0000-0002-4955-3226
authors.initials: C
authors.lastname: Brenner
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Lausanne CH-1015, Switzerland.|School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.
authors.forename: Carles
authors.identifier: 0000-0002-5167-7922
authors.initials: C
authors.lastname: Cantó
mesh_terms: D000818:Animals; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D008322:Mammals / Q000378:metabolism*; D018345:Mice, Knockout; D009243:NAD / Q000096:biosynthesis; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism; D009537:Nicotinamide Mononucleotide / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011726:Pyridinium Compounds
chemical_list: D011726:Pyridinium Compounds; C018613:nicotinamide-beta-riboside; D009243:NAD; D009537:Nicotinamide Mononucleotide; D009536:Niacinamide; D017853:Phosphotransferases (Alcohol Group Acceptor); C487431:NMRK1 protein, human; C000628188:Nmrk1 protein, mouse