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

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.