This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract Nicotinamide adenine dinucleotide (NAD + ) homeostasis is constantly compromised due to degradation by NAD + -dependent enzymes. NAD + replenishment by supplementation with the NAD + precursors

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... mide 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. K E Y W O R D S metabolism, NAD + , NMNH, nicotinamide mononucleotide 2 of 17 | ZAPATA-PÉREZ ET Al.