title: Regulation of NAD+ metabolism, signaling and compartmentalization in the yeast Saccharomyces cerevisiae.
abstract: Pyridine nucleotides are essential coenzymes in many cellular redox reactions in all living systems. In addition to functioning as a redox carrier, NAD(+) is also a required co-substrate for the conserved sirtuin deacetylases. Sirtuins regulate transcription, genome maintenance and metabolism and function as molecular links between cells and their environment. Maintaining NAD(+) homeostasis is essential for proper cellular function and aberrant NAD(+) metabolism has been implicated in a number of metabolic- and age-associated diseases. Recently, NAD(+) metabolism has been linked to the phosphate-responsive signaling pathway (PHO pathway) in the budding yeast Saccharomyces cerevisiae. Activation of the PHO pathway is associated with the production and mobilization of the NAD(+) metabolite nicotinamide riboside (NR), which is mediated in part by PHO-regulated nucleotidases. Cross-regulation between NAD(+) metabolism and the PHO pathway has also been reported; however, detailed mechanisms remain to be elucidated. The PHO pathway also appears to modulate the activities of common downstream effectors of multiple nutrient-sensing pathways (Ras-PKA, TOR, Sch9/AKT). These signaling pathways were suggested to play a role in calorie restriction-mediated beneficial effects, which have also been linked to Sir2 function and NAD(+) metabolism. Here, we discuss the interactions of these pathways and their potential roles in regulating NAD(+) metabolism. In eukaryotic cells, intracellular compartmentalization facilitates the regulation of enzymatic functions and also concentrates or sequesters specific metabolites. Various NAD(+)-mediated cellular functions such as mitochondrial oxidative phosphorylation are compartmentalized. Therefore, we also discuss several key players functioning in mitochondrial, cytosolic and vacuolar compartmentalization of NAD(+) intermediates, and their potential roles in NAD(+) homeostasis. To date, it remains unclear how NAD(+) and NAD(+) intermediates shuttle between different cellular compartments. Together, these studies provide a molecular basis for how NAD(+) homeostasis factors and the interacting signaling pathways confer metabolic flexibility and contribute to maintaining cell fitness and genome stability.
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, One Shields Ave., Davis, CA 95616, USA.
authors.forename: Michiko
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, One Shields Ave., Davis, CA 95616, USA. Electronic address: slin@ucdavis.edu.
authors.forename: Su-Ju
authors.initials: SJ
authors.lastname: Lin
mesh_terms: D002451:Cell Compartmentation; D003600:Cytosol / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000096:biosynthesis / Q000378:metabolism*; D009535:Nicotinamidase / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism; D056565:Sirtuin 2 / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism
chemical_list: D010710:Phosphates; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D009243:NAD; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D009535:Nicotinamidase; C474330:PNC1 protein, S cerevisiae
keywords: NAD(+) homeostasis; NAD(+) metabolism; NAD(+) signaling; Nicotinamide riboside; Yeasts
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