Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

After Ag encounter, CD8+ T cells become activated and begin to proliferate. Early during infection, when Ag-specific effector CD8+ T cells are proliferating, producing cytokines, and lysing infected cells in vivo, their mitochondrial potential is increased. The purpose of the experiments presented here was to determine whether mitochondrial function was required for CD8+ T cell function. To block mitochondrial function, transgenic CD8+ T cells were incubated with increasing doses of rotenone, an inhibitor of electron transport complex I. Within minutes of T cell activation, rotenone incubation decreased the production of H(2)O(2), calcium flux, and ERK1/2 phosphorylation. Failure to undergo signal transduction resulted in a decrease in T cell division initiated by peptide-coated cells, CD3/CD28 Abs, and PMA/ionomycin stimulation. Decreased function following rotenone incubation was not restricted to naive cells, as effector and memory CD8+ T cells isolated directly ex vivo from lymphocytic choriomeningitis virus-infected mice displayed decreased production of IFN-gamma and TNF-alpha production after peptide stimulation. Furthermore, incubation with rotenone decreased degranulation of effector and memory cells, a critical step in the cytolysis of infected cells. These data suggest that electron transport complex I is required for CD8+ T cell signal transduction, proliferation, cytokine production, and degranulation.
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PMID:Electron transport complex I is required for CD8+ T cell function. 1681 39

Recent advances in our understanding of tumor cell mitochondrial metabolism suggest it may be an attractive therapeutic target. Mitochondria are central hubs of metabolism that provide energy during the differentiation and maintenance of immune cell phenotypes. Mitochondrial membranes harbor several enzyme complexes that are involved in the process of oxidative phosphorylation, which takes place during energy production. Data suggest that, among these enzyme complexes, deficiencies in electron transport complex I may differentially affect immune responses and may contribute to the pathophysiology of several immunological conditions. Once activated by T cell receptor signaling, along with co-stimulation through CD28, CD4 T cells utilize mitochondrial energy to differentiate into distinct T helper (Th) subsets. T cell signaling activates Notch1, which is cleaved from the plasma membrane to generate its intracellular form (N1ICD). In the presence of specific cytokines, Notch1 regulates gene transcription related to cell fate to modulate CD4 Th type 1, Th2, Th17, and induced regulatory T cell (iTreg) differentiation. The process of differentiating into any of these subsets requires metabolic energy, provided by the mitochondria. We hypothesized that the requirement for mitochondrial metabolism varies between different Th subsets and may intersect with Notch1 signaling. We used the organic pesticide rotenone, a well-described complex I inhibitor, to assess how compromised mitochondrial integrity impacts CD4 T cell differentiation into Th1, Th2, Th17, and iTreg cells. We also investigated how Notch1 localization and downstream transcriptional capabilities regulation may be altered in each subset following rotenone treatment. Our data suggest that mitochondrial integrity impacts each of these Th subsets differently, through its influence on Notch1 subcellular localization. Our work further supports the notion that altered immune responses can result from complex I inhibition. Therefore, understanding how mitochondrial inhibitors affect immune responses may help to inform therapeutic approaches to cancer treatment.
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PMID:Rotenone Treatment Reveals a Role for Electron Transport Complex I in the Subcellular Localization of Key Transcriptional Regulators During T Helper Cell Differentiation. 2993 May 55

Aims: Carbon monoxide (CO) confers antiproliferative effects on T cells; however, how these effects are produced remains unclear. Reactive oxygen species (ROS) have recently emerged as important modulators of T cell proliferation. In this study, we aimed to determine whether the inhibitory effects of CO on T cell proliferation are dependent on the inhibition of ROS signaling. Results: Pretreatment with CO-releasing molecule-2 (CORM-2) had potent inhibitory effects on mouse T cell proliferation stimulated by anti-CD3/CD28 antibodies. Interestingly, CORM-2 pretreatment markedly suppressed intracellular ROS generation as well as the activity of NADPH oxidase and mitochondrial complexes I-IV in T cells after stimulation. The inhibitory effects of CORM-2 on both ROS production and T cell proliferation were comparable with those produced by the use of antioxidant N-acetylcysteine or a combined administration of mitochondrial complex I-IV inhibitors. Moreover, increasing intracellular ROS via hydrogen peroxide supplementation largely reversed the inhibitory effect of CORM-2 on the proliferation of T cells. The inhibitory effects of CORM-2 on both cell proliferation and intracellular ROS production were also shown in a T cell proliferation model involving stimulation by allogeneic dendritic cells or phorbol 12-myristate 13-actetate/ionomycin, as well as in spontaneous cell proliferation models in EL-4 and RAW264.7 cells. In addition, CORM-2 treatment significantly inhibited T cell activation in vivo and attenuated concanavalin A-induced autoimmune hepatitis. Innovation: CO inhibits T cell proliferation via suppression of intracellular ROS production. Conclusion: The study could supply a general mechanism to explain the inhibitory effects of CO on T cell activation and proliferation, favoring its future application in T cell-mediated diseases.
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PMID:Carbon Monoxide Inhibits T Cell Proliferation by Suppressing Reactive Oxygen Species Signaling. 3181 Mar 91