A genetic analysis of nitric oxide-mediated signaling during chronological aging in the yeast

Abstract

In mammals, NO•, a signaling molecule is implicated in the regulation of vasodilation, neurotransmission and immune response. It is believed that NO• is a signaling molecule also in unicellular organism like yeast and may be involved in the regulation of apoptosis and sporulation. It has been reported that NO• is produced during chronological aging (CA) leading to an increase of the superoxide level, which in turn mediates apoptosis. Since this conclusion was based on indirect measurements of NO• by the Griess reaction, the role of NO• signaling during CA in the yeast remains uncertain. We investigated this issue more precisely using different genetic and biochemical methodologies. We used cells lacking the factors influencing nitrosative stress response like flavohemoglobin metabolizing NO•, S-nitrosoglutathione reductase metabolizing S-nitrosoglutathione and the transcription factor Fzf1p mediating NO• response. We measured the standard parameters describing CA and found an elevation in the superoxide level, percentage of death cells, the level of TUNEL positive cells and a decrease in proliferating potential. These observations showed no significant differences between wild type cells and the disruptants except for a small elevation of the superoxide level in the Δsfa1 mutant. The intracellular NO• level and flavohemoglobin expression decreased rather than increased during CA. Products of general nitrogen metabolism and protein tyrosine nitration were slightly decreased during CA, the magnitude of changes showing no differences between the wild type and the mutant yeast. Altogether, our data indicate that apoptosis during yeast CA is mediated by superoxide signaling rather than NO• signaling.

Targeted Disruption of Inducible Nitric Oxide Synthase Protects Against Aging, S-Nitrosation, and Insulin Resistance in Muscle of Male Mice

“…Although several studies suggest that NO and iNOS could be involved in several aging-related diseases (2,6), the participation of these molecules on aging-induced insulin resistance is unclear. Here, we hypothesized that iNOS could mediate the insulin resistance through the S -nitrosation of insulin-signaling pathway proteins during aging.…”

Oxidative Stress and Programmed Cell Death in Yeast

“…In fact, studies have shown that ${\text{O}}_{\text{2}}^{\bullet -}$ detoxification mechanisms such as the superoxide dismutase enzymes (SODs), are essential for survival of S. cerevisiae against hyperoxia (Outten et al, 2005). Recently ${\text{O}}_{\text{2}}^{\bullet -}$ has also been implicated as a signaling molecule in yeast cell processes such as chronological aging (Weinberger et al, 2010; Lewinska et al, 2011). …”

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]. It has been suggested that yeast mitochondrial cytochrome c oxidase (COX) can catalyze the reduction of nitrite to NO [13], implying NO not from NOS may be employed for yeast signaling.…”