The Arylamine N-Acetyltransferases as Therapeutic Targets in Metabolic Diseases Associated with Mitochondrial Dysfunction

In humans, there are two arylamine N-acetyltransferase genes that encode functional enzymes (NAT1and NAT2) as well as one pseudogene, all of which are located together on chromosome 8. Although they were first identified by their role in the acetylation of drugs and other xenobiotics, recent studies have shown strong associations for both enzymes in a variety of diseases, including cancer, cardiovascular disease, and diabetes. There is growing evidence that this association may be causal. Consistently, NAT1 and NAT2 are shown to be required for healthy mitochondria. This review discusses the current literature on the role of both NAT1 and NAT2 in mitochondrial bioenergetics. It will attempt to relate our understanding of the evolution of the two genes with biologic function and then present evidence that several major metabolic diseases are influenced by NAT1 and NAT2. Finally, it will discuss current and future approaches to inhibit or enhance NAT1 and NAT2 activity/expression using small-molecule drugs.Significance StatementThe arylamine N-acetyltransferases (NATs) NAT1 and NAT2 share common features in their associations with mitochondrial bioenergetics. This review discusses mitochondrial function as it relates to health and disease, and the importance of NAT in mitochondrial function and dysfunction. It also compares NAT1 and NAT2 to highlight their functional similarities and differences. Both NAT1 and NAT2 are potential drug targets for diseases where mitochondrial dysfunction is a hallmark of onset and progression.