Cellular Compartmentation and the Redox/Nonredox Functions of NAD.

Nicotinamide adenine dinucleotide (NAD) spans diverse roles in biology, serving as both an important redox cofactor in metabolism and a substrate for signaling enzymes that regulate protein post-translational modifications (PTMs). Although the interactions between these different roles of NAD (and its reduced form NADH) have been considered, little attention has been paid to the role of compartmentation in these processes. Specifically, the role of NAD in metabolism is compartment specific (, mitochondrial cytosolic), affording a very different redox landscape for PTM-modulating enzymes such as sirtuins and poly(ADP-ribose) polymerases in different cell compartments. In addition, the orders of magnitude differences in expression levels between NAD-dependent enzymes are often not considered when assuming the effects of bulk changes in NAD levels on their relative activities. In this review, we discuss the metabolic, nonmetabolic, redox, and enzyme substrate roles of cellular NAD, and the recent discoveries regarding the interplay between these roles in different cell compartments. Therapeutic implications for the compartmentation and manipulation of NAD biology are discussed. 31, 623-642.