NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells

Joanna Ratajczak; Magali Joffraud; Samuel A.J. Trammell; Rosa Ras; Nuria Canela; Marie Boutant; Sameer S. Kulkarni; Marcelo Rodrigues; Philip Redpath; Marie E. Migaud; Johan Auwerx; Oscar Yanes; Charles Brenner; Carles Cantó

doi:10.1038/ncomms13103

NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells

Joanna Ratajczak, Magali Joffraud, Samuel A.J. Trammell, Rosa Ras, Nuria Canela, Marie Boutant, Sameer S. Kulkarni, Marcelo Rodrigues, Philip Redpath, Marie E. Migaud, Johan Auwerx, Oscar Yanes, Charles Brenner, Carles Cantó^*

^*Corresponding author af dette arbejde

131 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	13103
Tidsskrift	Nature Communications
Vol/bind	7
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms13103
Status	Udgivet - 11 okt. 2016

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Ratajczak, J., Joffraud, M., Trammell, S. A. J., Ras, R., Canela, N., Boutant, M., Kulkarni, S. S., Rodrigues, M., Redpath, P., Migaud, M. E., Auwerx, J., Yanes, O., Brenner, C., & Cantó, C. (2016). NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nature Communications, 7, Artikel 13103. https://doi.org/10.1038/ncomms13103

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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. ",

author = "Joanna Ratajczak and Magali Joffraud and Trammell, {Samuel A.J.} and Rosa Ras and Nuria Canela and Marie Boutant and Kulkarni, {Sameer S.} and Marcelo Rodrigues and Philip Redpath and Migaud, {Marie E.} and Johan Auwerx and Oscar Yanes and Charles Brenner and Carles Cant{\'o}",

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doi = "10.1038/ncomms13103",

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T1 - NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells

AU - Ratajczak, Joanna

AU - Joffraud, Magali

AU - Trammell, Samuel A.J.

AU - Ras, Rosa

AU - Canela, Nuria

AU - Boutant, Marie

AU - Kulkarni, Sameer S.

AU - Rodrigues, Marcelo

AU - Redpath, Philip

AU - Migaud, Marie E.

AU - Auwerx, Johan

AU - Yanes, Oscar

AU - Brenner, Charles

AU - Cantó, Carles

PY - 2016/10/11

Y1 - 2016/10/11

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms13103

DO - 10.1038/ncomms13103

M3 - Journal article

C2 - 27725675

AN - SCOPUS:84991294515

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 13103

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NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells

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