Nmnat1, encoding nicotinamide mononucleotide adenylyltransferase 1, is a key enzyme in the synthesis of nicotinamide adenine dinucleotide (NAD+), an essential cofactor in redox reactions involved in multiple cellular processes. NAD+ salvage pathway mediated by Nmnat1 is crucial, and Nmnat1 is vital to embryonic development [3]. Genetic models, such as knockout (KO) and conditional knockout (CKO) mice, have been instrumental in studying its functions.

In PT-specific Nmnat1 CKO mice, Nmnat1 deficiency led to mitoribosome excess, hindered mitoribosomal translation of oxidative phosphorylation complex proteins, and caused mitoribosomal dysfunction in the context of diabetic nephropathy, suggesting its protective role in this disease [1]. In human iPS cell-derived retinal organoid differentiation, NMNAT1-KO cells showed reduced induction of genes for retinal early development and failure of retinal primordial structure formation, indicating NMNAT1 is essential for retinal fate differentiation [2]. Hepatic Nmnat1 KO mice had lower NAD+ levels but comparable metabolic activity and similar phenotypes in diet-induced fatty liver disease models, suggesting redundancy in obesity-induced hepatic disorders [3]. Adipocyte-specific Nmnat1 KO mice had a marked reduction in nuclear NAD+ concentration in brown adipose tissue, yet no impact on thermogenic and metabolic responses [4].

In conclusion, Nmnat1 is essential for maintaining normal cellular functions, especially in relation to NAD+ synthesis. Studies using Nmnat1 KO/CKO mouse models have provided insights into its role in diseases like diabetic nephropathy, retinal degeneration, and have also shown its dispensability in certain metabolic contexts such as diet-induced fatty liver disease and regulation of thermogenesis in adipose tissue.