Reduced nicotinamide mononucleotide is a new and potent nad+ precursor in mammalian cells and mice

Rubén Zapata-Pérez, Alessandra Tammaro, Bauke V. Schomakers, Angelique M. L. Scantlebery, Simone Denis, Hyung L. Elfrink, Judith Giroud-Gerbetant, Carles Cantó, Carmen López-Leonardo, Rebecca L. McIntyre, Michel van Weeghel, Álvaro Sánchez-Ferrer, Riekelt H. Houtkooper

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47 Citations (Scopus)


Nicotinamide adenine dinucleotide (NAD+) homeostasis is constantly compromised due to degradation by NAD+-dependent enzymes. NAD+ replenishment by sup-plementation 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.
Original languageEnglish
Article numbere21456
Pages (from-to)1-17
Number of pages17
JournalFASEB Journal
Issue number4
Publication statusPublished - 1 Apr 2021


  • Metabolism
  • NAD
  • NMNH
  • Nicotinamide mononucleotide

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