Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor involved in various cellular biochemical reactions and contributes to the regulation of Ca2+ signaling, chromatin structure, DNA repair and lifespan. To date, how eukaryote cells transport and utilize NAD+ precursors as well as the signaling pathways that regulate NAD+ homeostasis remain unclear. Studying NAD+ homeostasis is also complicated by the complex and dynamic flexibility of precursors cells use to generate NAD+. Nicotinamide riboside (NR) and nicotinamide (NAM) are key pyridine metabolites that play important roles in maintaining NAD+ pools as well as calorie restriction (CR)-induced lifespan. To further understand the mechanisms of NAD+ homeostasis, we have established NR-specific and NAM-specific reporter genetic screen systems and identified yeast mutants with altered NAD+ metabolism. Our studies suggest that phosphate responsive PHO signaling and glucose signaling pathways contribute to controlling the NR branch of NAD+ metabolism. We have recently identified additional novel NAD+ homeostasis factors in the NAM branch. The current proposal builds on our recent studies of these factors and the interplay between components in NR/NAM/NAD+ metabolism and longevity-related nutrient signaling pathways. The long-term goal is to understand the mechanisms by which cells maintain NAD+ homeostasis in response to changes in growth conditions. The major hypothesis is that NAD+ homeostasis is modulated by nutrient-sensing signaling pathways, which play important roles in determining cell fitness and survival. Intracellular compartmentalization of NAD+ intermediates and homeostasis factors also contribute to the complex interplay of NAD+ homeostasis factors and nutrient sensing pathways.
The specific aims of the projects are:
Aim 1) To study how NAD+ precursor assimilation factors regulate NAD+ homeostasis, Aim 2) To study the cross-regulation of NAD+ homeostasis and nutrient sensing pathways, and Aim 3) To Identify and study novel NAD+ homeostasis factors in the NA/NAM salvage pathway. To achieve theses goals we will employ a combination of molecular genetics and biochemical methods to analyze genes, proteins and pathways involved. These studies will increase our understanding of how eukaryotic cells regulate NAD+ homeostasis in response to changes in growth conditions, and which longevity-related nutrient sensing signaling pathways are involved. Overall Significance: Our findings will contribute to the understanding of the molecular basis of the complex regulation of NAD+ homeostasis and cell life span as well as metabolic disorders related to aberrant NAD+ metabolism in human.
Relevance to public health: Niacin (vitamin B3, a NAD+ precursor) is widely used as a food supplement to improve heath. Administration of NAD+ precursors has also been shown to ameliorate human deficiencies related to aberrant NAD+ metabolism. This research utilizes the genetically amenable model system, budding yeast, to study the regulation of NAD+ homeostasis and signaling. Many components in NAD+ biosynthesis and metabolic pathways are conserved from yeast to mammals. Therefore, our findings are likely to provide insight into the development of therapeutic reagents for NAD+ deficiency-associated diseases such as diabetes and cancers, and also have broad implications for improving human nutrition and health.
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|Tsang, Felicia; Lin, Su-Ju (2015) Less is more: Nutrient limitation induces cross-talk of nutrient sensing pathways with NAD(+) homeostasis and contributes to longevity. Front Biol (Beijing) 10:333-357|
|Tsang, Felicia; James, Christol; Kato, Michiko et al. (2015) Reduced Ssy1-Ptr3-Ssy5 (SPS) signaling extends replicative life span by enhancing NAD+ homeostasis in Saccharomyces cerevisiae. J Biol Chem 290:12753-64|
|Kato, Michiko; Lin, Su-Ju (2014) Regulation of NAD+ metabolism, signaling and compartmentalization in the yeast Saccharomyces cerevisiae. DNA Repair (Amst) 23:49-58|
|Lin, Su-Ju; Austriaco, Nicanor (2014) Aging and cell death in the other yeasts, Schizosaccharomyces pombe and Candida albicans. FEMS Yeast Res 14:119-35|
|Kato, Michiko; Lin, Su-Ju (2014) YCL047C/POF1 is a novel nicotinamide mononucleotide adenylyltransferase (NMNAT) in Saccharomyces cerevisiae. J Biol Chem 289:15577-87|