%0 Journal Article %T Identification of Potential Calorie Restriction-Mimicking Yeast Mutants with Increased Mitochondrial Respiratory Chain and Nitric Oxide Levels %A Bin Li %A Craig Skinner %A Pablo R. Castello %A Michiko Kato %A Erin Easlon %A Li Xie %A Tianlin Li %A Shu-Ping Lu %A Chen Wang %A Felicia Tsang %A Robert O. Poyton %A Su-Ju Lin %J Journal of Aging Research %D 2011 %I Hindawi Publishing Corporation %R 10.4061/2011/673185 %X Calorie restriction (CR) induces a metabolic shift towards mitochondrial respiration; however, molecular mechanisms underlying CR remain unclear. Recent studies suggest that CR-induced mitochondrial activity is associated with nitric oxide (NO) production. To understand the role of mitochondria in CR, we identify and study Saccharomyces cerevisiae mutants with increased NO levels as potential CR mimics. Analysis of the top 17 mutants demonstrates a correlation between increased NO, mitochondrial respiration, and longevity. Interestingly, treating yeast with NO donors such as GSNO (S-nitrosoglutathione) is sufficient to partially mimic CR to extend lifespan. CR-increased NO is largely dependent on mitochondrial electron transport and cytochrome c oxidase (COX). Although COX normally produces NO under hypoxic conditions, CR-treated yeast cells are able to produce NO under normoxic conditions. Our results suggest that CR may derepress some hypoxic genes for mitochondrial proteins that function to promote the production of NO and the extension of lifespan. 1. Introduction Calorie restriction (CR) extends lifespan in a variety of organisms and has also been shown to ameliorate many age-associated diseases such as diabetes and cancers [1¨C3]. However, the molecular mechanisms underlying CR-induced beneficial effects are still not fully understood. Owing to a short lifespan and well-established molecular genetic techniques, the budding yeast Saccharomyces cerevisiae represents a powerful system to identify new components in CR signaling pathways and to study these factors at the molecular/genetic level. Yeast lifespan can be studied in two distinct ways: replicative lifespan (RLS) and chronological lifespan (CLS). RLS measures the number of cell divisions an individual yeast cell undergoes before senescence (division potential), whereas CLS measures the length of time cells remain viable at a nondividing state (postmitotic survival). RLS may serve as a model to understand the mechanisms of replicative senescence such as in stem cells, while CLS may be more relevant to postmitotic cell senescence in adult animals [4, 5]. Moderate CR can be imposed in yeast by reducing the glucose concentration from 2% to 0.5% in rich media [6¨C9], which extends both RLS and CLS. In yeast, CR is suggested to function through reducing the activities of conserved nutrient-sensing pathways. Decreasing the activities of the Ras-cAMP/PKA (cyclic AMP-activated protein kinase A) pathway, Sch9 (homolog of mammalian S6K kinases) and Tor1 kinases have been shown to mimic CR and extend %U http://www.hindawi.com/journals/jar/2011/673185/