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

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.

Automated summary

NMNH, as a new NAD(+) precursor, significantly increases NAD(+) levels and reduces damage through a unique metabolic pathway. Administration of NMNH in mice leads to a rapid surge in NAD(+) levels, demonstrating its potential for treating acute kidney injury.