FIGURE 1.

Overview of NAD⁺ metabolism in the heart. NAD⁺ is synthesized through the de novo pathway and the salvage pathway in mammalian cells. The de novo pathway generates NAD⁺ from Trp or NA. The salvage pathway, indicated by the thicker arrows, is the major NAD⁺ biosynthesis pathway in the heart where NAM generated from NAD⁺-consuming enzymes is converted into NMN through NAMPT – the rate limiting enzyme. NMN can also be generated from NR by NRK1/2. NMN is further converted into NAD⁺ by NMNAT1-3. A redox potential between NAD⁺ and its reduced form NADH is established by key catabolic processes including glycolysis, fatty acid β-oxidation and TCA cycle, which drives the electron transport chain (ETC). On the other hand, NAD⁺ is consumed by NAD⁺-consuming enzymes, including CD38 that generates cADPR, which is a Ca²⁺-mobilizing second messenger, PARP that catalyzes protein PARylation and SIRT that catalyzes protein deacetylation. These enzymatic reactions produce NAM as a byproduct that can be recycled back into NAD⁺ salvage pathway. In addition, NAD⁺ can also be consumed by NAD⁺ kinase which generates NADP⁺. Through CD38, NADP⁺ is further converted into NAADP, which is another Ca²⁺-mobilizing second messenger.