FIG. 2.

The dynamic regulation of intracellular NAD⁺ levels. Intracellular NAD⁺ levels are highly dynamic and are regulated by NAD⁺-producing and NAD⁺-consuming pathways as well as by cellular respiration. Three NAD⁺-producing pathways have been identified, which are the (i) de novo synthesis pathway (ii) the Preiss–Handler, and (iii) the NAD⁺-salvage pathway. Each pathway uses different precursor molecules and enzymes for the synthesis of NAD⁺. The precursor molecules surrounded by boxes are obtained from the diet. Similarly, three NAD⁺-consuming pathways have been identified and they include the (i) sirtuins (SIRTs) (ii) the PARPs, and (iii) the cADPR synthases known as CD38 and CD157, which are reported to exist both intra- and extracellularly (only depicted as extracellularly in the figure). NAD⁺ levels are further regulated by cellular redox reactions involved in cellular respiration, where NAD⁺ plays a role as a coenzyme. Enzymes of glycolysis reduce NAD⁺ in the cytoplasm, whereas the TCA cycle enzymes reduce additional NAD⁺ molecules in the mitochondria. Reducing equivalents of cytoplasmic NAD⁺ are then transferred to the mitochondrion through the G3P and MAS enzymes, ultimately reaching the electron transport chain complexes, where they get oxidized to generate the proton gradient necessary for ATP production. Another important factor regulating NAD⁺ not depicted in this figure is the circdian regulation of NAD⁺ by the circadian genes. cADPR, cyclic ADP ribose; G3P, glycerol-3-phoshate; CD38/157, ADP ribosyl cyclase/cyclic ADP ribose hydrolase 38/157; ETC, electron transport chain; MAS, malate–aspartate shuttle; NA, nicotinic acid; NAAD, nicotinic acid adenine dinucleotide; NAD⁺, nicotinamide adenine dinucleotide (oxidized form); NADH, nicotinamide adenine dinucleotide (reduced form); NADSYN, NAD synthetase; NAM, nicotinamide; NAMN, nicotinic acid mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinate phosphoribosyltransferase; NMN, nicotinamide mononucleotide; NMNAT, nicotinamide mononucleotide adenylyl transferase; NR, nicotinamide riboside; NRK, nicotinamide riboside kinase; PARPs, poly-ADP ribose transferases; QA, quinolinic acid; QPRT, quinolinate phosphoribosyl transferase; TCA cycle, tricarboxylic acid cycle; Trp, tryptophan.