Reduced nicotinamide mononucleotide is a new and potent NAD+ precursor in mammalian cells and mice. Issue 4 (16th March 2021)

• Record Type: Journal Article
• Authors: Zapata‐Pérez, Rubén; Tammaro, Alessandra; Schomakers, Bauke V.; Scantlebery, Angelique M. L.; Denis, Simone; Elfrink, Hyung L.; Giroud‐Gerbetant, Judith; Cantó, Carles; López‐Leonardo, Carmen; McIntyre, Rebecca L.; van Weeghel, Michel; Sánchez‐Ferrer, Álvaro; Houtkooper, Riekelt H.
• Is Part Of: FASEB journal. Volume 35:Issue 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-16
• Subjects: metabolism -- NAD+ -- NMNH -- nicotinamide mononucleotide; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202001826R
• Languages: English
• ISSNs: 0892-6638

Abstract

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.