NAD⁺ Homeostasis and Autophagy: Integrated Control Through Nutrient Signaling in Yeast and Mammals

Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite facilitating redox and biochemical reactions in many cellular processes. Maintaining NAD⁺ homeostasis is critical for proper cellular function, and abnormalities in NAD⁺ metabolism have been associated with various human diseases. However, the mechanisms underlying its regulation and interconnection with nutrient-sensing pathways remain incompletely understood. Recent studies show that autophagy, a conserved catabolic pathway essential for cellular homeostasis, plays an important role in maintaining the NAD⁺ pool. NAD⁺ may also impact autophagy through its regulation of cellular metabolism and sirtuins, a family of NAD⁺-dependent deacetylases. Given the complexity of these pathways, their mechanistic interconnection is not fully understood. Here, we discuss studies examining the interactions of NAD⁺ metabolism, autophagy, and nutrient-sensing pathways, with a focus on the budding yeast Saccharomyces cerevisiae and connections to mammalian systems. We also discuss the role of sirtuins in these pathways and the impacts of NAD⁺ precursor supplementation. This review provides insights into how nutrient-sensing pathways may mediate the co-regulation of NAD⁺, autophagy, and cellular homeostasis. The studies discussed provide the basis for the development of future research directions that may inform potential therapeutic targets for human disorders associated with the dysregulation of NAD⁺ metabolism and autophagy.