Central Nodes for Cellular NAD+ Metabolism
In normal circumstances, most NAD+ or NMN in blood is converted to NR, which enters the cell through specific transporters and is metabolized into NMN through NRK activity. Similarly, circulating NAM can be metabolized to NMN extracellulary by the extracellular NAMPT or enter the cell and be metabolized into NMN by the intracellular NAMPT. Extracellular NA can also enter the cell and be converted to NAD+ via a three-step reaction that is reliant on NAPRT, NMNAT, and NADSYN. NMN and, possibly, NAM are potentially transported into the mitochondrial and nuclear compartments. In those compartments, NMN can lead to NAD+ synthesis via NMNAT activity. In each subcellular compartment, NAD+ and NADH equilibriums will be determined by their unique redox states. In the mitochondria, the ETC is a major contributor to NADH oxidation into NAD+, coupling this action to ATP synthesis. In addition, the mitochondria and the cytosol can exchange redox equivalents through the malate/aspartate (M/A) and glyceraldehyde 3-phosphate (G3P) shuttles. In all compartments, the activity of NAD+-consuming enzymes, such as sirtuins or PARPs, lead to NAM production, which can be salvaged for NAD+ synthesis via NAMPT activity. Dashed arrows indicate pathways that need further validation.