Interplay between compartmentalized NAD⁺ synthesis and consumption: a focus on the PARP family

Nicotinamide adenine dinucleotide (NAD + ) is an essential cofactor for redox enzymes, but also moonlights as a substrate for signaling enzymes. When used as a substrate by signaling enzymes, it is consumed, necessitating the recycling of NAD + consumption products (i.e., nicotinamide) via a salvage pathway in order to maintain NAD + homeostasis. A major family of NAD + consumers in mammalian cells are poly-ADP-ribose-polymerases (PARPs). PARPs comprise a family of 17 enzymes in humans, 16 of which catalyze the transfer of ADP-ribose from NAD + to macromolecular targets (namely, proteins, but also DNA and RNA). Because PARPs and the NAD + biosynthetic enzymes are subcellularly localized, an emerging concept is that the activity of PARPs and other NAD + consumers are regulated in a compartmentalized manner. In this review, I discuss NAD + metabolism, how different subcellular pools of NAD + are established and regulated, and how free NAD + levels can control signaling by PARPs and redox metabolism.