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  • 1
    Keywords: YEAST SACCHAROMYCES-CEREVISIAE ; MAMMALIAN-CELLS ; OXIDATIVE STRESS ; ENDOPLASMIC-RETICULUM ; DISULFIDE BOND FORMATION ; FLUORESCENT PROTEIN INDICATORS ; OUTER-MEMBRANE ; 2-OXOGLUTARATE CARRIERS ; INTACT MITOCHONDRIA ; ANCILLARY ROLE
    Abstract: Glutathione is an important mediator and regulator of cellular redox processes. Detailed knowledge of local glutathione redox potential (E(GSH)) dynamics is critical to understand the network of redox processes and their influence on cellular function. Using dynamic oxidant recovery assays together with E(GSH)-specific fluorescent reporters, we investigate the glutathione pools of the cytosol, mitochondrial matrix and intermembrane space (IMS). We demonstrate that the glutathione pools of IMS and cytosol are dynamically interconnected via porins. In contrast, no appreciable communication was observed between the glutathione pools of the IMS and matrix. By modulating redox pathways in the cytosol and IMS, we find that the cytosolic glutathione reductase system is the major determinant of E(GSH) in the IMS, thus explaining a steady-state E(GSH) in the IMS which is similar to the cytosol. Moreover, we show that the local E(GSH) contributes to the partially reduced redox state of the IMS oxidoreductase Mia40 in vivo. Taken together, we provide a comprehensive mechanistic picture of the IMS redox milieu and define the redox influences on Mia40 in living cells.
    Type of Publication: Journal article published
    PubMed ID: 22705944
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  • 2
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    Biological Chemistry 393 (9), 999-1004 
    Keywords: CELLS ; IN-VIVO ; GLUTATHIONE ; MITOCHONDRIA ; OXIDATIVE STRESS ; HYDROGEN-PEROXIDE ; REACTIVE OXYGEN ; CYSTEINE RESIDUES ; FLUORESCENT ; PROTEIN THIOLS
    Abstract: Redox reactions are at the heart of bioenergetics, yet their biological role is not restricted to metabolism. One specific focus of contemporary Redox Biology is the study of how the folding, stability, activity, and interactivity of proteins are subject to redox control. Key questions pertain to the chemical nature of physiological redox changes and their exact location inside the cell, the nature and distribution of protein redox modifications, and their meaning for cellular physiology. In recent years, Redox Biology has developed novel methodological directions, for example, the proteomic profiling of protein redox modifications and the noninvasive monitoring of redox processes in vivo. These and other approaches allow asking new questions for which the answers are almost completely unknown. To stimulate exchange of technical knowledge and the appreciation of Redox Biology in general, the German Society for Biochemistry and Molecular Biology (GBM) recently founded a Study Group for Redox Biology.
    Type of Publication: Journal article published
    PubMed ID: 22944698
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  • 3
    Keywords: CELLS ; GENE-EXPRESSION ; PROTEINS ; ACTIVATION ; TRANSCRIPTION FACTOR ; specificity ; OXIDATIVE STRESS ; ENDOPLASMIC-RETICULUM ; CHEMISTRY ; HYDROGEN-PEROXIDE
    Abstract: Hydrogen peroxide (H2O2) acts as a signaling messenger by oxidatively modifying distinct cysteinyl thiols in distinct target proteins. However, it remains unclear how redox-regulated proteins, which often have low intrinsic reactivity towards H2O2 (kapp approximately 1-10 M-1 s-1), can be specifically and efficiently oxidized by H2O2. Moreover, cellular thiol peroxidases, which are highly abundant and efficient H2O2 scavengers, should effectively eliminate virtually all of the H2O2 produced in the cell. Here, we show that the thiol peroxidase peroxiredoxin-2 (Prx2), one of the most H2O2-reactive proteins in the cell (kapp approximately 107-108 M-1 s-1), acts as a H2O2 signal receptor and transmitter in transcription factor redox regulation. Prx2 forms a redox relay with the transcription factor STAT3 in which oxidative equivalents flow from Prx2 to STAT3. The redox relay generates disulfide-linked STAT3 oligomers with attenuated transcriptional activity. Cytokine-induced STAT3 signaling is accompanied by Prx2 and STAT3 oxidation and is modulated by Prx2 expression levels.
    Type of Publication: Journal article published
    PubMed ID: 25402766
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  • 4
    Keywords: DISEASES ; HEALTH ; GLUTATHIONE ; PROBES ; OXIDATIVE STRESS ; SELENIUM ; POLLUTANTS ; KeyWords Plus: FLUORESCENT PROTEIN INDICATORS
    Abstract: Background: The toxicity of many xenobiotic compounds is believed to involve oxidative injury to cells. Direct assessment of mechanistic events involved in xenobiotic-induced oxidative stress is not easily achievable. Development of genetically encoded probes designed for monitoring intracellular redox changes represents a methodological advance with potential applications in toxicological studies.Objective: We tested the utility of redox-sensitive green fluorescent protein (roGFP)-based redox sensors for monitoring real-time intracellular redox changes induced by xenobiotics in toxicological studies.Methods: roGFP2, a reporter of the glutathione redox potential (EGSH), was used to monitor EGSH in cultured human airway epithelial cells (BEAS-2B cells) undergoing exposure to 0.15-1.0 ppm ozone (O3). Cells were imaged in real time using a custom-built O3 exposure system coupled to a confocal microscope.Results: O3 exposure induced a dose- and time-dependent increase of the cytosolic EGSH. Additional experiments confirmed that roGFP2 is not directly oxidized, but properly equilibrates with the glutathione redox couple: Inhibition of endogenous glutaredoxin 1 (Grx1) disrupted roGFP2 responses to O3, and a Grx1-roGFP2 fusion protein responded more rapidly to O3 exposure. Selenite-induced up-regulation of GPx (glutathione peroxidase) expression-enhanced roGFP2 responsiveness to O3, suggesting that (hydro)peroxides are intermediates linking O3 exposure to glutathione oxidation.Conclusion: Exposure to O3 induces a profound increase in the cytosolic EGSH of airway epithelial cells that is indicative of an oxidant-dependent impairment of glutathione redox homeostasis. These studies demonstrate the utility of using genetically encoded redox reporters in making reliable assessments of cells undergoing exposure to xenobiotics with strong oxidizing properties.
    Type of Publication: Journal article published
    PubMed ID: 23249900
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  • 5
    Keywords: CELLS ; METABOLISM ; BIOLOGY ; DROSOPHILA-MELANOGASTER ; LIFE-SPAN ; OXIDATIVE STRESS ; MATRIX ; REDUCTASE ; FLUORESCENT PROTEIN INDICATORS ; Cytosol ; mitochondrial
    Abstract: The glutathione redox couple (GSH/GSSG) and hydrogen peroxide (H(2)O(2)) are central to redox homeostasis and redox signaling, yet their distribution within an organism is difficult to measure. Using genetically encoded redox probes in Drosophila, we establish quantitative in vivo mapping of the glutathione redox potential (E(GSH)) and H(2)O(2) in defined subcellular compartments (cytosol and mitochondria) across the whole animal during development and aging. A chemical strategy to trap the in vivo redox state of the transgenic biosensor during specimen dissection and fixation expands the scope of fluorescence redox imaging to include the deep tissues of the adult fly. We find that development and aging are associated with redox changes that are distinctly redox couple-, subcellular compartment-, and tissue-specific. Midgut enterocytes are identified as prominent sites of age-dependent cytosolic H(2)O(2) accumulation. A longer life span correlated with increased formation of oxidants in the gut, rather than a decrease.
    Type of Publication: Journal article published
    PubMed ID: 22100409
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  • 6
    Keywords: CELLS ; EXPRESSION ; PATHWAY ; METABOLISM ; MICE ; OXIDATIVE STRESS ; inflammation ; HYDROGEN-PEROXIDE ; IRON REGULATORY PROTEIN-1 ; HUMAN-NEUTROPHILS
    Abstract: The peptide hormone hepcidin regulates mammalian iron homeostasis by blocking ferroportin-mediated iron export from macrophages and the duodenum. During inflammation, hepcidin is strongly induced by interleukin 6, eventually leading to the anemia of chronic disease. Here we show that hepatoma cells and primary hepatocytes strongly up-regulate hepcidin when exposed to low concentrations of H(2)O(2) (0.3-6 mum), concentrations that are comparable with levels of H(2)O(2) released by inflammatory cells. In contrast, bolus treatment of H(2)O(2) has no effect at low concentrations and even suppresses hepcidin at concentrations of 〉50 mum. H(2)O(2) treatment synergistically stimulates hepcidin promoter activity in combination with recombinant interleukin-6 or bone morphogenetic protein-6 and in a manner that requires a functional STAT3-responsive element. The H(2)O(2)-mediated hepcidin induction requires STAT3 phosphorylation and is effectively blocked by siRNA-mediated STAT3 silencing, overexpression of SOCS3 (suppressor of cytokine signaling 3), and antioxidants such as N-acetylcysteine. Glycoprotein 130 (gp130) is required for H(2)O(2) responsiveness, and Janus kinase 1 (JAK1) is required for adequate basal signaling, whereas Janus kinase 2 (JAK2) is dispensable upstream of STAT3. Importantly, hepcidin levels are also increased by intracellular H(2)O(2) released from the respiratory chain in the presence of rotenone or antimycin A. Our results suggest a novel mechanism of hepcidin regulation by nanomolar levels of sustained H(2)O(2). Thus, similar to cytokines, H(2)O(2) provides an important regulatory link between inflammation and iron metabolism.
    Type of Publication: Journal article published
    PubMed ID: 22932892
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