Identification of Potential Calorie Restriction-Mimicking Yeast Mutants with Increased Mitochondrial Respiratory Chain and Nitric Oxide Levels

Abstract

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.

Artemisinin mimics calorie restriction to extend yeast lifespan via a dual-phase mode: a conclusion drawn from global transcriptome profiling

“…As supporting evidence, the NO donor compound S-nitrosoglutathione indeed confers yeast lifespan extension [10]. However, no NOS homologs have been identified in all known yeast strains although NO has been detected in Saccharomyces cerevisiae [11] and Schizosaccharomyces pombe [12].…”

Calorie Restriction, Mitochondria and Longevity in Saccharomyces cerevisiae

“…The electron transport chain (ETC) is a major site of ROS generation (Figure 14.1), and dysfunction of the ETC can result in electron leakage, causing oxidative damage to nearby proteins, mitochondrial DNA, and lipids, and perpetuating a vicious cycle wherein more damages to the ETC generate more ROS, and furthers oxidative damage inside and outside the mitochondria. Mitochondrial function decreases as we age (Wei et al 2009), and disruption of the ETC in budding yeast has a dramatic negative impact upon both measurements of life span, both in unrestricted and calorie-restricted cells (Lin et al 2002;Li et al 2011). However, there is a dynamic balance between low levels of specific ROS, which can serve as a signal to activate the oxidative and general stress responses, and dangerously high levels of ROS, which can lead to cell death.…”

“…Additionally, studies from fission yeast Shizosaccharomyces pombe suggest that certain mitogenactivated protein kinases (MAPKs), important in stress signaling, may be essential for CR-induced CLS (Zuin et al 2010). Furthermore, recent studies suggest that increases in specific ROS in calorie-restricted cells may be important for life span maintenance during CR, particularly hydrogen peroxide (H 2 O 2 ) (Mesquita et al 2010) and nitric oxide (NO) (Li et al 2011). One of the most daunting challenges for the field of aging research is to unravel the myriad of interactions between the CR downstream pathways.…”

“…Mitochondrial respiration is greatly increased in cells on mild CR (Lin et al 2002;Easlon et al 2007), and functional respiration is essential for extended CLS (Li et al 2011). Functional respiration is also necessary to realize the full life span potential of CR in RLS (Lin et al 2002), although CR may have some respiration-independent benefits as well, at least under severe CR (0.05% glucose) Easlon et al 2007).…”

“…However, there is a dynamic balance between low levels of specific ROS, which can serve as a signal to activate the oxidative and general stress responses, and dangerously high levels of ROS, which can lead to cell death. The optimal level of ROS for longevity varies greatly between organisms: in budding yeast; disruption of the ETC usually results in extremely short CLS (Barros et al 2004;Li et al 2011), whereas in C. elegans, postdevelopment RNAi conducted on certain respiratory genes results in much higher ROS and considerable life span extension (Dillin et al 2002;Lee et al 2003). It is likely that increased mitochondrial stability, increased respiration, and a primed oxidative stress response each play a role in CR-mediated life span extension, and together promote metabolism and physiology optimized for longevity.…”