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Reduced nicotinamide mononucleotide is a new and potent NAD(+) precursor in mammalian cells and mice

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Autor(es):
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Zapata-Perez, Ruben [1] ; Tammaro, Alessandra [2] ; Schomakers, Bauke V. [1, 3] ; Scantlebery, Angelique M. L. [1] ; Denis, Simone [1] ; Elfrink, Hyung L. [1, 3] ; Giroud-Gerbetant, Judith [4] ; Canto, Carles [4] ; Lopez-Leonardo, Carmen [5] ; McIntyre, Rebecca L. [1] ; van Weeghel, Michel [1, 3] ; Sanchez-Ferrer, Alvaro [6] ; Houtkooper, Riekelt H. [1]
Número total de Autores: 13
Afiliação do(s) autor(es):
[1] Univ Amsterdam, Amsterdam UMC, Amsterdam Gastroenterol Endocrinol & Metab, Lab Genet Metab Dis, Amsterdam Cardiovasc Sci, Meibergdreef 9, Amsterdam - Netherlands
[2] Univ Amsterdam, Amsterdam UMC, Pathol Dept, Amsterdam - Netherlands
[3] Univ Amsterdam, Amsterdam UMC, Core Facil Metabol, Amsterdam - Netherlands
[4] Nestle Res, Nestle Inst Hlth Sci, Lausanne - Switzerland
[5] Univ Murcia, Dept Organ Chem, Murcia - Spain
[6] Univ Murcia, Dept Biochem & Mol Biol A, Murcia - Spain
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: FASEB JOURNAL; v. 35, n. 4 APR 2021.
Citações Web of Science: 0
Resumo

Nicotinamide adenine dinucleotide (NAD(+)) homeostasis is constantly compromised due to degradation by NAD(+)-dependent enzymes. NAD(+) replenishment by supplementation with the NAD(+) precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) can alleviate this imbalance. However, NMN and NR are limited by their mild effect on the cellular NAD(+) pool and the need of high doses. Here, we report a synthesis method of a reduced form of NMN (NMNH), and identify this molecule as a new NAD(+) precursor for the first time. We show that NMNH increases NAD(+) levels to a much higher extent and faster than NMN or NR, and that it is metabolized through a different, NRK and NAMPT-independent, pathway. We also demonstrate that NMNH reduces damage and accelerates repair in renal tubular epithelial cells upon hypoxia/reoxygenation injury. Finally, we find that NMNH administration in mice causes a rapid and sustained NAD(+) surge in whole blood, which is accompanied by increased NAD(+) levels in liver, kidney, muscle, brain, brown adipose tissue, and heart, but not in white adipose tissue. Together, our data highlight NMNH as a new NAD(+) precursor with therapeutic potential for acute kidney injury, confirm the existence of a novel pathway for the recycling of reduced NAD(+) precursors and establish NMNH as a member of the new family of reduced NAD(+) precursors. (AU)