Hlavata 2008 Aging Cell
|Hlavatá L, Nachin L, Jezek P, Nyström T (2008) Elevated Ras/protein kinase A activity in Saccharomyces cerevisiae reduces proliferation rate and lifespan by two different reactive oxygen species-dependent routes. Aging Cell 7:148-57.|
Abstract: Cells with overactive RAS/protein kinase A (PKA) signaling, such as RAS2Val19 cells, exhibit reduced proliferation rates and accelerated replicative senescence. We show here that the extended generation time of RAS2Val19cells 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 RAS2Val19 cells. In contrast, overproducing functional Aac2p restored proliferation but not longevity of RAS2Val19 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.
• Keywords: ATP/ADP carrier, ATP synthase, Lifespan, Oncogenic RAS, Proliferation, Reactive oxygen species
• O2k-Network Lab: CZ Prague Jezek P
Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Aging;senescence Stress:Oxidative stress;RONS Organism: Saccharomyces cerevisiae, Fungi
Coupling state: OXPHOS