Article

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: 6.34). 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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Available from: Lydie Plecitá-Hlavatá, Jan 19, 2015
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    • "Previous studies in yeast have established links between Ras signaling and mitochondrial function, via cAMP/PKA dependent and independent routes [16,17]. Within yeast Ras/cAMP/PKA signaling also controls cellular processes that include cell growth and proliferation and the induction of stress responses [18], making this pathway a good candidate to integrate environmental signaling with mitochondrial regulation. "
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    • "Ras pathway activity is an important component in the regulation of cellular longevity in eukaryotic cells. The expression of a constitutively active form of Ras has been shown to result in the accumulation of reactive oxygen species (ROS) and a reduction in the life span in yeast and mammalian cells (Heeren et al., 2004; Hlavata et al., 2008; Serrano et al., 1997). The ability of the RascAMP-PKA pathway to regulate mitochondrial function and ROS production also appears to have been harnessed by a fungal apoptotic response. "
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    • "Conversely, treating cells with hydrogen peroxide (H2O2) decreases the level of NAD+, decreases the activity of SIRT1, and lead to the accumulation of acetylated p53.48 While longevity genetic manipulations decrease the ROS level, short-lived mutants such as activated Ras2 increased the intracellular ROS level.49,50 Therefore, mathematically modeling the intracellular homeostasis of NAD/NADH, NADP/NADPH, GSH/GSSG, ROS, and calcium will highlight the contribution of involved proteins. "
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