The Roles of Moonlighting Nicotinamide Mononucleotide Adenylyl Transferases in Cell Physiology

Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite, and abnormal NAD⁺ metabolism has been linked to numerous human diseases. The nicotinamide mononucleotide adenylyl transferases (NMNATs) catalyze NAD⁺ production through both de novo and salvage pathways. NMNATs are multi-functional enzymes with NAD⁺ synthesis activity and chaperone activity. Interestingly, NMNATs are involved in neuroprotection, and whether these neuroprotective effects require NAD⁺ synthesis activity appears to vary depending on the context. Nevertheless, NMNATs can modulate cellular processes primarily through supporting NAD⁺ homeostasis. In this review, we discuss the roles of NMNATs in NAD⁺ homeostasis, their functional domains, and how their subcellular localizations influence the compartmentalized NAD⁺ pools. We present an integrative framework to help understand the diverse impacts of NMNATs in human diseases, with a focus on neurological disorders caused by different insults. To address knowledge gaps, we integrate the regulation of NMNATs in both human and model organisms. We also discuss the current understanding and limitations of NMNAT activators and inhibitors to help evaluate their translational significance as therapeutic targets for NAD⁺ modulation.