Redox control of yeast Sir2 activity is involved in acetic acid resistance and longevity

Yeast Sir2 is an NAD-dependent histone deacetylase related to oxidative stress and aging. In a previous study, we showed that Sir2 is regulated by S-glutathionylation of key cysteine residues located at the catalytic domain. Mutation of these residues results in strains with increased resistance to disulfide stress. In the present study, these mutant cells were highly resistant to acetic acid and had an increased chronological life span. Mutant cells had increased acetyl-CoA synthetase activity, which converts acetic acid generated by yeast metabolism to acetyl.CoA. This could explain the acetic acid resistance and lower levels of this toxic acid in the extracellular media during aging. Increased acetyl-CoA levels would raise lipid droplets, a source of energy during aging, and fuel glyoxylate-dependent gluconeogenesis. The key enzyme of this pathway, phosphoenolpyruvate carboxykinase (Pck1), showed increased activity in these Sir2 mutant cells during aging. Sir2 activity decreased when cells shifted to the diauxic phase in the mutant strains, compared to the WT strain. Since Pck1 is inactivated through Sir2-dependent deacetylation, the decline in Sir2 activity explained the rise in Pck1 activity. As a consequence, storage of sugars such as trehalose would increase. We conclude that extended longevity observed in the mutants was a combination of increased lipid droplets and trehalose, and decreased acetic acid in the extracellular media. These results offer a deeper understanding of the redox regulation of Sir2 in acetic acid resistance, which is relevant in some food and industrial biotechnology and also in the metabolism associated to calorie restriction, aging and pathologies such as diabetes.