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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: FASEB JOURNAL; v. 35, n. 4 APR 2021.
• Web of Science Citations: 0

Abstract

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)