Diversification of NAD biological role: the importance of location

Over 100 years after its first discovery, several new aspects of the biology of the redox co-factor NAD are rapidly emerging. NAD, as well as its precursors, its derivatives, and its metabolic enzymes, have been recently shown to play a determinant role in a variety of biological functions, from the classical role in oxidative phosphorylation and redox reactions to a role in regulation of gene transcription, lifespan and cell death, from a role in neurotransmission to a role in axon degeneration, and from a function in regulation of glucose homeostasis to that of control of circadian rhythm. It is also becoming clear that this variety of specialized functions is regulated by the fine subcellular localization of NAD, its related nucleotides and its metabolic enzymatic machinery. Here we describe the known NAD biosynthetic and catabolic pathways, and review evidence supporting a specialized role for NAD metabolism in a subcellular compartment-dependent manner.