The oncogenic RAS2val19 mutation locks respiration, independently of PKA, in a mode prone to generate ROS

Abstract

The RAS2val19 allele, which renders the cAMP-PKA pathway constitutively active and decreases the replicative life-span of yeast cells, is demonstrated to increase production of reactive oxygen species (ROS) and to elevate oxidative protein damage. Mitochondrial respiration in the mutant is locked in a nonphosphorylating mode prone to generate ROS but this phenotype is not linked to a constitutively active PKA pathway. In contrast, providing RAS2val19 cells with the mammalian uncoupling protein UCP1 restores phosphorylating respiration and reduces ROS levels, but does not correct for PKA-dependent defects. Thus, the RAS2val19 allele acts like a double-edged sword with respect to oxidation management: (i) it diminishes expression of STRE element genes required for oxidative stress defenses in a PKA-dependent fashion, and (ii) it affects endogenous ROS production and the respiratory state in a PKA-independent way. The effect of the oncogenic RAS allele on the replicative life-span is primarily asserted via the PKA-dependent pathway since Pde2p, but not UCP1, overproduction suppressed premature aging of the RAS2val19 mutant.