Cross-talk in NAD⁺ metabolism: insights from Saccharomyces cerevisiae

NAD⁺ (nicotinamide adenine dinucleotide) is an essential metabolite involved in a myriad of cellular processes. The NAD⁺ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human with some species-specific differences. Studying the regulation of NAD⁺ metabolism has been difficult due to the dynamic flexibility of NAD⁺ intermediates, the redundancy of biosynthesis pathways, and the complex interconnections among them. The budding yeast Saccharomyces cerevisiae provides an efficient genetic model for the isolation and study of factors that regulate specific NAD⁺ biosynthesis pathways. A recent study has uncovered a putative cross-regulation between the de novo NAD⁺ biosynthesis and copper homeostasis mediated by a copper-sensing transcription factor Mac1. Mac1 appears to work with the Hst1-Sum1-Rfm1 complex to repress the expression of de novo NAD⁺ biosynthesis genes. Here, we extend the discussions to include additional nutrient- and stress-sensing pathways that have been associated with the regulation of NAD⁺ homeostasis. NAD⁺ metabolism is an emerging therapeutic target for several human diseases. NAD⁺ preservation also helps ameliorate age-associated metabolic disorders. Recent findings in yeast contribute to the understanding of the molecular basis underlying the cross-regulation of NAD⁺ metabolism and other signaling pathways.