title: Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments.
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.
authors.affiliation: 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.
authors.forename: Janine
authors.initials: J
authors.lastname: Kirstein
authors.affiliation: Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Morito
authors.affiliation: Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Kakihana
authors.affiliation: Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto, Japan.
authors.forename: Munechika
authors.initials: M
authors.lastname: Sugihara
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Minnen
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hipp
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Nussbaum-Krammer
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Prasad
authors.initials: P
authors.lastname: Kasturi
authors.affiliation: 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.
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Hartl
authors.affiliation: 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.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagata
authors.affiliation: 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.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism*
keywords: ER; ageing; proteostasis; redox homeostasis