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

Janine Kirstein*, Daisuke Morito, Taichi Kakihana, Munechika Sugihara, Anita Minnen, Mark S. Hipp, Carmen Nussbaum-Krammer, Prasad Kasturi, F. Ulrich Hartl, Kazuhiro Nagata, Richard I Morimoto

*Corresponding author for this work

Research output: Contribution to journalArticle

47 Scopus citations

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. Synopsis Using genetically encoded sensors this study shows that the opposing redox state in ER lumen and cytosol is altered during ageing and upon disruption of proteostasis. The resulting redox imbalance can spread across tissues. Genetically encoded redox sensors report on tissue- and compartment-specific redox state in C. elegans and HeLa cells. Young animals have an oxidized ER that changes towards more reducing conditions during ageing, whereas the cytosol is reducing in young animals and becomes oxidizing with the progression of ageing. Proteotoxic challenges such as the inhibition of the proteasome or protein aggregates provoke a similar response and also act in a trans-compartmental manner. The organellar redox homeostasis is regulated across tissues and responds to proteotoxic challenges in a distal tissue. Using genetically encoded sensors this study shows that the opposing redox state in ER lumen and cytosol is altered during ageing and upon disruption of proteostasis. The resulting redox imbalance can spread across tissues.

Original languageEnglish (US)
Pages (from-to)2334-2349
Number of pages16
JournalEMBO Journal
Volume34
Issue number18
DOIs
StatePublished - Sep 1 2015

Keywords

  • ER
  • ageing
  • proteostasis
  • redox homeostasis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Kirstein, J., Morito, D., Kakihana, T., Sugihara, M., Minnen, A., Hipp, M. S., Nussbaum-Krammer, C., Kasturi, P., Hartl, F. U., Nagata, K., & Morimoto, R. I. (2015). Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments. EMBO Journal, 34(18), 2334-2349. https://doi.org/10.15252/embj.201591711