Loss of Cytochrome c Oxidase Promotes RAS-Dependent ROS Production from the ER Resident NADPH Oxidase, Yno1p, in Yeast
Loss of Cytochrome c Oxidase Promotes RAS-Dependent ROS Production from the ER Resident NADPH Oxidase, Yno1p, in Yeast
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DOI：
10.1016/j.cmet.2013.07.005
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发表时间：
2013-08-06
期刊：
影响因子：
29
通讯作者：
Gourlay, Campbell W.
中科院分区：
文献类型：
--
作者：
Leadsham, Jane E.;Sanders, Geraldine;Gourlay, Campbell W.
许多疾病状态，包括衰老过程，都与携带呼吸功能障碍的线粒体的积累有关。线粒体功能障碍通常伴随着ROS水平的增加，这可能导致细胞功能障碍和疾病病因。在这里，我们使用模式真核生物S。研究细胞色素c氧化酶（考克斯）活性的降低是否导致线粒体产生ROS。我们提供的证据表明，虽然减少考克斯复合物的活性与ROS的积累，线粒体不是主要的生产中心。相反，我们表明，COX-缺陷的线粒体激活Ras在其外膜上，通过抑制抗氧化防御和ERAD介导的ER定位的NADPH氧化酶Yno 1 p的周转，建立了一个pro-ROS积累环境。我们的数据表明，功能失调的线粒体可以作为一个信号平台，以促进氧化还原稳态的丧失，ROS积累，并加速老化的酵母。
Many disease states, including the aging process, are associated with the accumulation of mitochondria harboring respiratory dysfunction. Mitochondrial dysfunction is often accompanied by increased ROS levels that can contribute to cellular dysfunction and disease etiology. Here we use the model eukaryote S. cerevisiae to investigate whether reduced cytochrome c oxidase (COX) activity, commonly reported in aging organisms and associated with neurodegenerative disorders, leads to ROS production from mitochondria. We provide evidence that although reduced COX complex activity correlates with ROS accumulation, mitochondria are not the major production center. Instead we show that COX-deficient mitochondria activate Ras upon their outer membrane that establishes a pro-ROS accumulation environment by suppressing antioxidant defenses and the ERAD-mediated turnover of the ER-localized NADPH oxidase Yno1p. Our data suggest that dysfunctional mitochondria can serve as a signaling platform to promote the loss of redox homeostasis, ROS accumulation, and accelerate aging in yeast.