title: Mitochondria-derived hydrogen peroxide selectively enhances T cell receptor-initiated signal transduction.
abstract: T cell receptor (TCR)-initiated signal transduction is reported to increase production of intracellular reactive oxygen species, such as superoxide (O2˙(-)) and hydrogen peroxide (H2O2), as second messengers. Although H2O2 can modulate signal transduction by inactivating protein phosphatases, the mechanism and the subcellular localization of intracellular H2O2 as a second messenger of the TCR are not known. The antioxidant enzyme superoxide dismutase (SOD) catalyzes the dismutation of highly reactive O2˙(-) into H2O2 and thus acts as an intracellular generator of H2O2. As charged O2˙(-) is unable to diffuse through intracellular membranes, cells express distinct SOD isoforms in the cytosol (Cu,Zn-SOD) and mitochondria (Mn-SOD), where they locally scavenge O2˙(-) leading to production of H2O2. A 2-fold organelle-specific overexpression of either SOD in Jurkat T cell lines increases intracellular production of H2O2 but does not alter the levels of intracellular H2O2 scavenging enzymes such as catalase, membrane-bound peroxiredoxin1 (Prx1), and cytosolic Prx2. We report that overexpression of Mn-SOD enhances tyrosine phosphorylation of TCR-associated membrane proximal signal transduction molecules Lck, LAT, ZAP70, PLCγ1, and SLP76 within 1 min of TCR cross-linking. This increase in mitochondrial H2O2 specifically modulates MAPK signaling through the JNK/cJun pathway, whereas overexpressing Cu,Zn-SOD had no effect on any of these TCR-mediated signaling molecules. As mitochondria translocate to the immunological synapse during TCR activation, we hypothesize this translocation provides the effective concentration of H2O2 required to selectively modulate downstream signal transduction pathways.
authors.affiliation: From the Division of Gastroenterology and Liver Disease, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4952.
authors.forename: Tejpal
authors.initials: T
authors.lastname: Gill
authors.affiliation: From the Division of Gastroenterology and Liver Disease, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4952. Electronic address: alan.levine@case.edu.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Levine
mesh_terms: D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D013481:Superoxides / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D011948:Receptors, Antigen, T-Cell; D013481:Superoxides; D006861:Hydrogen Peroxide; C515940:PRDX1 protein, human; C086065:PRDX2 protein, human; D054464:Peroxiredoxins; D013482:Superoxide Dismutase; D011494:Protein Kinases
keywords: Cytosolic SOD (Cu,Zn-SOD); Hydrogen Peroxide; Jun N-terminal Kinase (JNK); Jun Transcription Factor; Mitochondria; Mitochondrial SOD (Mn-SOD); Signal Transduction; T Cell Receptor; T Lymphocyte