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EMBO J. 2015 Sep 14;34(18):2334-49. doi: 10.15252/embj.201591711. Epub 2015 Jul 29.

Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments.

Author information

1
Leibniz-Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin, Berlin, Germany kirstein@fmp-berlin.de uhartl@biochem.mpg.de nagata@cc.kyoto-su.ac.jp r-morimoto@northwestern.edu.
2
Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto, Japan.
3
Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA.
4
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
5
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany kirstein@fmp-berlin.de uhartl@biochem.mpg.de nagata@cc.kyoto-su.ac.jp r-morimoto@northwestern.edu.
6
Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto, Japan kirstein@fmp-berlin.de uhartl@biochem.mpg.de nagata@cc.kyoto-su.ac.jp r-morimoto@northwestern.edu.
7
Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA kirstein@fmp-berlin.de uhartl@biochem.mpg.de nagata@cc.kyoto-su.ac.jp r-morimoto@northwestern.edu.

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.

KEYWORDS:

ER; ageing; proteostasis; redox homeostasis

PMID:
26228940
PMCID:
PMC4570520
DOI:
10.15252/embj.201591711
[Indexed for MEDLINE]
Free PMC Article

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