Elevated Ras/protein kinase A activity in Saccharomyces cerevisiae reduces proliferation rate and lifespan by two different reactive oxygen species-dependent routes.
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.
Hlavatá
Lydie
L
Institute of Physiology, Czech Academy of Sciences, CZ-142 20 Prague, Czech Republic.
Nachin
Laurence
L
Jezek
Petr
P
Nyström
Thomas
T
D049109:Cell Proliferation; D016922:Cellular Senescence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D005818:Genetic Engineering; D000226:Mitochondrial ADP, ATP Translocases / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism; D050505:Mutant Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000096:biosynthesis; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D050505:Mutant Proteins; C112225:PET9 protein, S cerevisiae; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D000226:Mitochondrial ADP, ATP Translocases; D013482:Superoxide Dismutase; D017868:Cyclic AMP-Dependent Protein Kinases; D018631:ras Proteins