SOD2 Functions Downstream of Sch9 to Extend Longevity in Yeast

Abstract

Signal transduction pathways inactivated during periods of starvation are implicated in the regulation of longevity in organisms ranging from yeast to mammals, but the mechanisms responsible for life-span extension are poorly understood. Chronological life-span extension in S. cerevisiae cyr1 and sch9 mutants is mediated by the stress-resistance proteins Msn2/Msn4 and Rim15. Here we show that mitochondrial superoxide dismutase (Sod2) is required for survival extension in yeast. Deletion of SOD2 abolishes life-span extension in sch9Δ mutants and decreases survival in cyr1:mTn mutants. The overexpression of Sods—mitochondrial Sod2 and cytosolic CuZnSod (Sod1)—delays the age-dependent reversible inactivation of mitochondrial aconitase, a superoxide-sensitive enzyme, and extends survival by 30%. Deletion of the RAS2 gene, which functions upstream of CYR1, also doubles the mean life span by a mechanism that requires Msn2/4 and Sod2. These findings link mutations that extend chronological life span in S. cerevisiae to superoxide dismutases and suggest that the induction of other stress-resistance genes regulated by Msn2/4 and Rim15 is required for maximum longevity extension.

Screening of selected ageing-related proteins that extend chronological life span in yeast Saccharomyces cerevisiae

“…1 b). In accordance with previous reports, overexpression of control protein Sod1 10 or Ump1 37 increased CLS, while overexpression of Aim14 decreased CLS 38 in the primary screen. The extensions of yeast CLS by the seven overexpressed proteins were verified in the confirmatory screen (Fig.…”

“…Certain proteins are known to regulate longevity and stress response during chronological ageing 9 , 10 , 39 . To examine the stress response of yeast cells with overexpressed Ptc4, Zwf1, Sme1 or Sod1 after prolonged ageing in stressed conditions, thermal and oxidative stress assays were conducted.…”

“…In contrast, CLS regulation can also be investigated by overexpressing proteins in S. cerevisiae . As an example, overexpression of both Sod1 and Sod2 was shown to extend CLS of S. cerevisiae by 30%, however the overexpression of either Sod1 or Sod2 alone could only lead to minor CLS extension in budding yeast 10 . In addition, overexpression of Sir2 also extended CLS in S. cerevisiae 11 .…”

“…The downregulation of two nutrient signalling pathways, target of rapamycin (TOR) and cyclic adenosine monophosphate dependent protein kinase A (cAMP-PKA), was reported to extend longevity by activating Rim15, a downstream target converged by the two pathways 23 – 25 . Activated Rim15 then induces the activation of the stress-resistance transcription factors Gis1 and Msn2/4 that promote cellular resistance towards stresses such as osmotic stress, thermal stress, oxidative stress and nutrient starvation, leading to CLS extension 2 , 9 , 10 , 23 – 26 . Such findings show that the increase of stress tolerance factors contributes to CLS extension.…”

The Role of Sch9 and the V-ATPase in the Adaptation Response to Acetic Acid and the Consequences for Growth and Chronological Lifespan

“…This is in line with previously published results, showing that stationary phase sch9∆ cells are more resistant to high concentrations of acetic acid [11]. As the transcription factors Gis1 and Msn2/4, which control the the expression of superoxide dismutases and catalases, are well-studied downstream targets that are under negative control of Sch9 [62,63], it is not surprising that the sch9∆ strain displays a general lower accumulation of DHE positive cells and an enhanced longevity. Still, when sch9∆ cells were grown in the presence of 150 mM acetic acid, a delay in ROS accumulation can be noticed, similar as observed in WT cells.…”