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 discussNAD⁺ metabolism, how different subcellular pools of NAD⁺ are established and regulated, and how free NAD⁺ levels can control signaling by PARPs and redox metabolism.