title: Multiple glutathione disulfide removal pathways mediate cytosolic redox homeostasis.
abstract: Glutathione is central to cellular redox chemistry. The majority of glutathione redox research has been based on the chemical analysis of whole-cell extracts, which unavoidably destroy subcellular compartment-specific information. Compartment-specific real-time measurements based on genetically encoded fluorescent probes now suggest that the cytosolic glutathione redox potential is about 100 mV more reducing than previously thought. Using these probes in yeast, we show that even during severe oxidative stress, the cytosolic glutathione disulfide (GSSG) concentration is much more tightly regulated than expected and provides a mechanistic explanation for the discrepancy with conventional measurements. GSSG that is not immediately reduced in the cytosol is rapidly transported into the vacuole by the ABC-C transporter Ycf1. The amount of whole-cell GSSG is entirely dependent on Ycf1 and uninformative about the cytosolic glutathione pool. Applying these insights, we identify Trx2 and Grx2 as efficient backup systems to glutathione reductase for cytosolic GSSG reduction.
authors.affiliation: Division of Redox Regulation, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Bruce
authors.initials: B
authors.lastname: Morgan
authors.forename: Daria
authors.initials: D
authors.lastname: Ezeriņa
authors.forename: Theresa N E
authors.initials: TN
authors.lastname: Amoako
authors.forename: Jan
authors.initials: J
authors.lastname: Riemer
authors.forename: Matthias
authors.initials: M
authors.lastname: Seedorf
authors.forename: Tobias P
authors.initials: TP
authors.lastname: Dick
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D054477:Glutaredoxins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000737:chemistry*; D005982:Glutathione Transferase / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D010084:Oxidation-Reduction; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors; D014617:Vacuoles / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D054477:Glutaredoxins; C527885:Grx2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C516110:TRX2 protein, S cerevisiae; C089179:YCF1 protein, S cerevisiae; D013879:Thioredoxins; D005982:Glutathione Transferase; D005978:Glutathione; D019803:Glutathione Disulfide