Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments
Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments
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DOI：
10.15252/embj.201591711
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发表时间：
2015-09-01
期刊：
影响因子：
11.4
通讯作者：
Morimoto, Richard I.
中科院分区：
文献类型：
--
作者：
Kirstein, Janine;Morito, Daisuke;Morimoto, Richard I.
细胞蛋白质稳态网络整合了真核细胞多个亚细胞区室中的蛋白质折叠和清除机制。内质网（ER）是膜蛋白和分泌蛋白合成和折叠的场所。ER的一个显著特征是其严格控制的氧化还原稳态，这是形成分子间和分子内二硫键所必需的。采用基因编码的体内传感器报告的氧化还原状态的细胞器特异性的方式，我们表明，在线虫秀丽隐杆线虫的ER的氧化还原状态受到深刻的变化，在蠕虫的寿命。在年轻的动物中，ER是氧化的，并且在衰老过程中向还原状态转变，而在胞质溶胶中，氧化还原状态随着年龄的增长变得更加氧化。同样，在C. elegans和HeLa细胞揭示了氧化还原稳态的保守性。此外，我们表明，细胞器的氧化还原稳态调节跨组织内C。为生物体的适应性提供了一种新的测量方法。
The cellular proteostasis network integrates the protein folding and clearance machineries in multiple sub-cellular compartments of the eukaryotic cell. The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins. A distinctive feature of the ER is its tightly controlled redox homeostasis necessary for the formation of inter-and intra-molecular disulphide bonds. Employing genetically encoded in vivo sensors reporting on the redox state in an organelle-specific manner, we show in the nematode Caenorhabditis elegans that the redox state of the ER is subject to profound changes during worm lifetime. In young animals, the ER is oxidizing and this shifts towards reducing conditions during ageing, whereas in the cytosol the redox state becomes more oxidizing with age. Likewise, the redox state in the cytosol and the ER change in an opposing manner in response to proteotoxic challenges in C. elegans and in HeLa cells revealing conservation of redox homeostasis. Moreover, we show that organelle redox homeostasis is regulated across tissues within C. elegans providing a new measure for organismal fitness.