Fig. 1

NAD⁺ metabolism. NAD⁺ levels are maintained by three independent biosynthetic pathways. The de novo synthesis pathway converts tryptophan to quinolinic acid (QA) via a series of enzymatic steps, in which indoleamine-2,3-dioxygenase (IDO) is a rate-limiting enzyme that catalyzes the first step and the conversion of QA to nicotinate mononucleotide (NAMN) is the ultimate bottleneck step catalyzed by quinolinate phosphoribosyltransferase (QPRT). The Preiss-Handler pathway uses dietary nicotinic acid (NA) to generate NAMN through nicotinate phosphoribosyltransferase (NAPRT). NAMN is converted to NAD⁺ by the sequential actions of nicotinamide mononucleotide adenylyl transferases (NMNATs) and NAD⁺ synthetase (NADSYN). The NAD⁺ salvage pathway recycles nicotinamide (NAM) generated as a by-product of the enzymatic activities of NAD⁺-consuming proteins (sirtuins, poly(ADP-ribose) polymerases (PARPs) and the NAD⁺ glycohydrolases CD38, CD157 and SARM1), into nicotinamide mononucleotide (NMN) via the rate-limiting enzyme NAM phosphoribosyltransferase (NAMPT). NMN is then converted into NAD⁺ via the different NMNATs. These renascent NAD⁺ receives a hydride to yield the reduced form NADH, thereby driving various metabolic processes including glycolysis, the tricarboxylic acid (TCA) cycle and β-oxidation of fatty acids. On the contrary, NADH provides an electron pair to drive oxidative phosphorylation (OXPHOS) for the generation of ATP in the mitochondria and the conversion of lactate to pyruvate in the cytoplasm, which are accompanied by intracellular NAD⁺ regeneration.