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Media type:
E-Article
Title:
Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments
Contributor:
Kirstein, Janine;
Morito, Daisuke;
Kakihana, Taichi;
Sugihara, Munechika;
Minnen, Anita;
Hipp, Mark S;
Nussbaum‐Krammer, Carmen;
Kasturi, Prasad;
Hartl, F Ulrich;
Nagata, Kazuhiro;
Morimoto, Richard I
imprint:
Springer Science and Business Media LLC, 2015
Published in:The EMBO Journal
Language:
English
DOI:
10.15252/embj.201591711
ISSN:
1460-2075;
0261-4189
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:p>The cellular proteostasis network integrates the protein folding and clearance machineries in multiple sub‐cellular compartments of the eukaryotic cell. The endoplasmic reticulum (<jats:styled-content style="fixed-case">ER</jats:styled-content>) is the site of synthesis and folding of membrane and secretory proteins. A distinctive feature of the <jats:styled-content style="fixed-case">ER</jats:styled-content> is its tightly controlled redox homeostasis necessary for the formation of inter‐ and intra‐molecular disulphide bonds. Employing genetically encoded <jats:italic>in vivo</jats:italic> sensors reporting on the redox state in an organelle‐specific manner, we show in the nematode <jats:italic>Caenorhabditis elegans</jats:italic> that the redox state of the <jats:styled-content style="fixed-case">ER</jats:styled-content> is subject to profound changes during worm lifetime. In young animals, the <jats:styled-content style="fixed-case">ER</jats:styled-content> 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 <jats:styled-content style="fixed-case">ER</jats:styled-content> change in an opposing manner in response to proteotoxic challenges in <jats:italic>C. elegans</jats:italic> and in HeLa cells revealing conservation of redox homeostasis. Moreover, we show that organelle redox homeostasis is regulated across tissues within <jats:italic>C. elegans</jats:italic> providing a new measure for organismal fitness.</jats:p>