title: The glutathione reductase GSR-1 determines stress tolerance and longevity in Caenorhabditis elegans.
abstract: Glutathione (GSH) and GSH-dependent enzymes play a key role in cellular detoxification processes that enable organism to cope with various internal and environmental stressors. However, it is often not clear, which components of the complex GSH-metabolism are required for tolerance towards a certain stressor. To address this question, a small scale RNAi-screen was carried out in Caenorhabditis elegans where GSH-related genes were systematically knocked down and worms were subsequently analysed for their survival rate under sub-lethal concentrations of arsenite and the redox cycler juglone. While the knockdown of γ-glutamylcysteine synthetase led to a diminished survival rate under arsenite stress conditions, GSR-1 (glutathione reductase) was shown to be essential for survival under juglone stress conditions. gsr-1 is the sole GSR encoding gene found in C. elegans. Knockdown of GSR-1 hardly affected total glutathione levels nor reduced glutathione/glutathione disulphide (GSH/GSSG) ratio under normal laboratory conditions. Nevertheless, when GSSG recycling was impaired by gsr-1(RNAi), GSH synthesis was induced, but not vice versa. Moreover, the impact of GSSG recycling was potentiated under oxidative stress conditions, explaining the enormous effect gsr-1(RNAi) knockdown had on juglone tolerance. Accordingly, overexpression of GSR-1 was capable of increasing stress tolerance. Furthermore, expression levels of SKN-1-regulated GSR-1 also affected life span of C. elegans, emphasising the crucial role the GSH redox state plays in both processes.
authors.affiliation: Department of Molecular Physiology, Institute for Animal Physiology, University of Muenster, Muenster, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Lüersen
authors.forename: Dirk
authors.initials: D
authors.lastname: Stegehake
authors.forename: Jens
authors.initials: J
authors.lastname: Daniel
authors.forename: Mike
authors.initials: M
authors.lastname: Drescher
authors.forename: Irene
authors.initials: I
authors.lastname: Ajonina
authors.forename: Caroline
authors.initials: C
authors.lastname: Ajonina
authors.forename: Patrick
authors.initials: P
authors.lastname: Hertel
authors.forename: Christian
authors.initials: C
authors.lastname: Woltersdorf
authors.forename: Eva
authors.initials: E
authors.lastname: Liebau
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects; D009285:Naphthoquinones / Q000633:toxicity; D016877:Oxidants / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D034622:RNA Interference; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D018053:Arsenites; D029742:Caenorhabditis elegans Proteins; D009285:Naphthoquinones; D016877:Oxidants; D005980:Glutathione Reductase; D005978:Glutathione; C015001:arsenite; C005134:juglone