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  • 1
    Keywords: NF-KAPPA-B ; SYSTEMIC-LUPUS-ERYTHEMATOSUS ; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ; KINASE-C-THETA ; OXYGEN SPECIES PRODUCTION ; MANGANESE SUPEROXIDE-DISMUTASE ; ADP-DEPENDENT GLUCOKINASE ; COMPLEX-I DEFICIENCY ; ALVEOLAR EPITHELIAL-CELLS ; HYDROGEN-PEROXIDE UPTAKE
    Abstract: Early scientific reports limited the cell biological role of reactive oxygen species (ROS) to the cause of pathological damage. However, extensive research performed over the last decade led to a wide recognition of intracellular oxidative/redox signaling as a crucial mechanism of homeostatic regulation. Amongst different cellular processes known to be influenced by redox signaling, T-cell activation is one of the most established. Numerous studies reported an indispensible role for ROS as modulators of T-cell receptor-induced transcription. Nevertheless, mechanistic details regarding signaling pathways triggered by ROS are far from being delineated. The nature and interplay between enzymatic sources involved in the generation of "oxidative signals" are also a matter of ongoing research. In particular, active participation of the mitochondrial respiratory chain as ROS producer constitutes an intriguing issue with various implications for bioenergetics of activated T cells as well as for T-cell-mediated pathologies. The aim of the current review is to address these interesting concepts.
    Type of Publication: Journal article published
    PubMed ID: 23749029
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  • 2
    Keywords: EXPRESSION ; NF-KAPPA-B ; PROTEIN-KINASE ; NADPH OXIDASE ; DEHYDROGENASE ; HYDROGEN-PEROXIDE ; PYRUVATE-KINASE ; RECEPTOR STIMULATION ; LYMPHOCYTE-PROLIFERATION ; ROS PRODUCTION
    Abstract: Mitochondria-originating reactive oxygen species control T cell receptor (TCR)-induced gene expression. Here, we show that TCR-triggered activation of ADP-dependent glucokinase (ADPGK), an alternative, glycolytic enzyme typical for Archaea, mediates generation of the oxidative signal. We also show that ADPGK is localized in the endoplasmic reticulum and suggest that its active site protrudes toward the cytosol. The ADPGK-driven increase in glycolytic metabolism coincides with TCR-induced glucose uptake, downregulation of mitochondrial respiration, and deviation of glycolysis toward mitochondrial glycerol-3-phosphate dehydrogenase (GPD) shuttle; i.e., a metabolic shift to aerobic glycolysis similar to the Warburg effect. The activation of respiratory-chain-associated GPD2 results in hyperreduction of ubiquinone and reactive oxygen species release from mitochondria. In parallel, mitochondrial bioenergetics and ultrastructure are altered. Downregulation of ADPGK or GPD2 abundance inhibits oxidative signal generation and induction of NF-kappaB-dependent gene expression, whereas overexpression of ADPGK potentiates them.
    Type of Publication: Journal article published
    PubMed ID: 23168256
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  • 3
    Keywords: CANCER CELLS ; EXPRESSION ; NF-KAPPA-B ; TUMOR-NECROSIS-FACTOR ; T cell activation ; T-CELLS ; TRANSCRIPTION FACTORS ; MITOCHONDRIA ; NADPH OXIDASE ; KINETICS ; FACTOR-ALPHA ; HYDROGEN-PEROXIDE ; COMPLEX-I ; LYMPHOCYTE-ACTIVATION ; RECEPTOR STIMULATION ; reactive oxygen species (ROS) ; Activation-induced cell death (AICD) ; IL-2 and CD95L/FasL ; Manganese superoxide dismutase (MnSOD/SOD2)
    Abstract: Mitochondrial reactive oxygen species (ROS) are indispensible for T cell activation-induced expression of interleukin 2 (IL-2) and CD95 ligand (CD95L, FasL/Apo-1L) genes, and in turn, for CD95L-mediated activation-induced cell death (AICD). Here, we show that manganese superoxide dismutase (MnSOD/SOD2), a major mitochondrial antioxidative enzyme, constitutes an important control switch in the process of activation-induced oxidative signal generation in T cells. Analysis of the kinetics of T cell receptor (TCR)-triggered ROS production revealed a temporal association between higher MnSOD abundance/activity and a shut-down phase of oxidative signal generation. Transient or inducible MnSOD overexpression abrogated T cell activation-triggered mitochondrial ROS production as well as NF-kappaB- and AP-1-mediated transcription. Consequently, lowered expression of IL-2 and CD95L genes resulted in decreased IL-2 secretion and CD95L-dependent AICD. Moreover, upregulation of the mitochondrial MnSOD level is dependent on oxidation-sensitive transcription and not on the increase of mitochondrial mass. Thus, MnSOD-mediated negative feedback regulation of activation-induced mitochondrial ROS generation exemplifies a process of retrograde mitochondria-to-nucleus communication. Our finding underlines the critical role for MnSOD and mitochondria in the regulation of human T cell activation.
    Type of Publication: Journal article published
    PubMed ID: 22429591
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