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Elevated Ras/protein kinase A activity in Saccharomyces cerevisiae reduces proliferation rate and lifespan by two different reactive oxygen species-dependent routes. Aging Cell 7:148-157

Institute of Physiology, Czech Academy of Sciences, CZ-142 20 Prague, Czech Republic.
Aging cell (Impact Factor: 5.94). 04/2008; 7(2):148-57. DOI: 10.1111/j.1474-9726.2007.00361.x
Source: PubMed

ABSTRACT 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.

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    • "Mitochondria derived from a cyc3 mutant with reduced cytochrome c activity produced the highest level of H 2 O 2 , while appreciable levels of H 2 O 2 were released from mitochondria isolated from mutants affected in complex III and IV function. Elevated RAS/protein kinase A (PKA) pathway signalling has been shown to lead to increased ROS production and decreased ATP/ADP carrier activity, due to damage accumulation [89]. Over-expression of SOD1 suppressed these effects, highlighting the role of the superoxide anion in decreased ATP/ADP carrier activity. "
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