Open AccessElevated Ras/protein kinase A activity in Saccharomyces cerevisiae reduces proliferation rate and lifespan by two different reactive oxygen species‐dependent routes
Author(s) -
Hlavatá Lydie,
Nachin Laurence,
Ježek Petr,
Nyström Thomas
Publication year - 2008
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2007.00361.x
Subject(s) - reactive oxygen species , biology , mitochondrial ros , mitochondrion , microbiology and biotechnology , protein kinase a , kinase , superoxide dismutase , biochemistry , fragmentation (computing) , oxidative stress , ecology
Summary Cells with overactive RAS /protein kinase A (PKA) signaling, such as RAS2 Val19 cells, exhibit reduced proliferation rates and accelerated replicative senescence. We show here that the extended generation time of RAS2 Val19 cells is the result of abrogated ATP/ADP carrier activity of the mitochondria. Both PKA‐dependent and independent routes are responsible for inhibiting ATP/ADP exchange in the RAS ‐overactive cells. The reduced carrier activity is due, at least in part, to elevated levels of reactive oxygen species (ROS), which also cause a proteolysis‐dependent fragmentation of the Aac2p carrier both in vivo and on isolated mitochondria. Attenuated carrier activity is suppressed by overproducing the superoxide dismutase, Sod1p, and this enhances both the proliferation rate and the replicative longevity of RAS2 Val19 cells. In contrast, overproducing functional Aac2p restored proliferation but not longevity of RAS2 Val19 cells. Thus, Ras signaling affects proliferation rate and replicative lifespan by two different, ROS‐dependent, routes. While the reduction in generation time is linked to the inactivation, specifically, of the mitochondrial nucleotide carrier, longevity is affected by other, and hitherto unknown, target(s) of ROS attack.