Fig. 2.

Subcellular equilibrium of NAD⁺. The NAD⁺ homeostasis is maintained by the biosynthesis, consumption and recycling in differentiate subcellular compartments including the cytosol, the nucleus and the mitochondria. NAD⁺ precursors including Trp, NA, NR, NMN and NAM are metabolized into NAD⁺ via Preiss-Handler pathway, de novo pathway and salvage pathway, respectively. NAD⁺ can receive hydride to yield the reduced form NADH in the metabolic processes including glycolysis, FAO, and the TCA cycle. NADH provides an electron pair to drive the mitochondrial OXPHOS for the generation of ATP and the conversion of lactic acid to pyruvate. The cytosolic and mitochondrial NADH is exchanged through the malate-aspartate shuttle and glycerol-3-phosphate shuttle, while the cytosolic and mitochondrial NADPH is exchanged by the isocitrate-a-KG shuttle. NAD⁺ can also be phosphorylated into NADP⁺ by NAD⁺ kinases including nicotinamide nucleotide transhydrogenase (NNT) and NAD kinases (NADKs). Cytosolic NADP⁺ is reduced into NADPH by G6PD and 6PGD in the pentose phosphate pathway, and by ME1 in the conversion of malate to pyruvate. Mitochondrial NADPH is produced by IDH2, GLUD, NNT and ME3. The NADPH is required for the activation of NOXs and the synthesis of palmitate. Abbreviation: α-KGDH, alpha-ketoglutarate dehydrogenase; GLUD, glutamate dehydrogenase; NNT, nicotinamide nucleotide transhydrogenase; G3PDH, glyceraldehyde 3-phosphate dehydrogenase; 6PGD, 6-phosphogluconate dehydrogenase; G6PD, glucose-6-phosphate dehydrogenase; GPx, glutathione peroxidases; IDH1/2, isocitrate dehydrogenase 1 and 2; MDH, malate dehydrogenase; ME1/3, malic enzyme; NADK, NAD⁺ kinase; NOXs, NADPH oxidases; OXPHOS, oxidative phosphorylation; PPP, pentose phosphate pathway; PRx, peroxiredoxin; SDH, succinate dehydrogenase; SOD1-3, superoxide dismutase type 1-3; TCA cycle, tricarboxylic acid cycle; GSH, Glutathione; LDH, Lactate dehydrogenase