Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments |
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| Authors: | Munechika Sugihara Anita Minnen Mark S Hipp Carmen Nussbaum‐Krammer F Ulrich Hartl Kazuhiro Nagata Richard I Morimoto |
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| Affiliation: | 1. Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kita‐ku, Kyoto, Japan;2. Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA;3. Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany |
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| Abstract: | 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. |
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| Keywords: | ageing
ER
proteostasis redox homeostasis |
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