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The oncogenic RAS2 val19 mutation locks respiration, independently of PKA, in a mode prone to generate ROS
Author(s) -
Hlavatá Lydie,
Aguilaniu Hugo,
Pichová Alena,
Nyström Thomas
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg314
Subject(s) - biology , reactive oxygen species , phosphorylation , oxidative phosphorylation , mutant , mitochondrial ros , microbiology and biotechnology , mitochondrion , oxidative stress , mutation , protein kinase a , allele , biochemistry , gene
The RAS2 val19 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. Mito chondrial respiration in the mutant is locked in a non‐phosphorylating mode prone to generate ROS but this phenotype is not linked to a constitutively active PKA pathway. In contrast, providing RAS2 val19 cells with the mammalian uncoupling protein UCP1 restores phosphorylating respiration and reduces ROS levels, but does not correct for PKA‐dependent defects. Thus, the RAS2 val19 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 RAS2 val19 mutant.