Elevated Ras/protein kinase A activity in Saccharomyces cerevisiae reduces proliferation rate and lifespan by two different reactive oxygen species-dependent routes
Elevated Ras/protein kinase A activity in Saccharomyces cerevisiae reduces proliferation rate and lifespan by two different reactive oxygen species-dependent routes
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DOI：
10.1111/j.1474-9726.2007.00361.x
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发表时间：
2008-04-01
期刊：
影响因子：
7.8
通讯作者：
Nystrom, Thomas
中科院分区：
文献类型：
--
作者：
Hlavata, Lydie;Nachin, Laurence;Nystrom, Thomas
具有过度活跃的RAS/蛋白激酶A（PKA）信号传导的细胞，例如RAS 2（Val 19）细胞，表现出降低的增殖速率和加速的复制性衰老。我们在这里表明，RAS 2（Val 19）细胞的世代时间延长是废除ATP/ADP载体活性的线粒体的结果。PKC依赖性和非依赖性途径都负责抑制RAS过度激活细胞中的ATP/ADP交换。降低的载体活性至少部分是由于活性氧（ROS）水平升高，这也导致Aac 2 p载体在体内和分离的线粒体上的蛋白水解依赖性片段化。衰减的载体活性被抑制过量生产的超氧化物歧化酶，Sod 1 p，这提高了RAS 2（Val 19）细胞的增殖速率和复制寿命。相反，过量产生功能性Aac 2 p恢复了RAS 2（Val 19）细胞的增殖，但没有恢复其寿命。因此，Ras信号通过两种不同的ROS依赖性途径影响增殖速率和复制寿命。虽然世代时间的减少与线粒体核苷酸载体的失活有关，但寿命受到其他迄今为止未知的活性氧攻击靶点的影响。
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.