NAD+ metabolism (Homo sapiens)

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NAD+ metabolism in different cellular compartments. The different precursors to intracellular NAD metabolism—tryptophan, nicotinic acid (NA), nicotinamide, NR, and NMN—are shown, along with their extra- cellular metabolism by CD38 and CD73. The cytoplasmic and nuclear NAD+ pools probably equilibrate by diffusion through the nuclear pore. However, the mitochondrial membrane is impermeable to both NAD+ and NADH. Reducing equivalents generated by glycolysis are transferred to the mitochondrial matrix via the malate/aspartate shuttle and the glyceraldehyde-3-phosphate shuttle. The resulting mitochondrial NADH (malate/aspartate shuttle) is oxidized by complex I in the respiratory chain (ETC), whereas the resulting FADH2 (glyceraldehyde-3-phosphate shuttle) is oxidized by complex II. In each of the three compartments, different NAD+-consuming enzymes lead to the generation of nicotinamide, which is recycled via the NAD+ salvage pathway. Different forms of the NMNAT enzyme and sirtuins are localized in different compartments. The nature of the salvage pathway for NAD+ in mitochondria has not been fully resolved, although NMNAT3 has been found in mitochondria. NADK, NAD+ kinase.