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  • 1
    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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  • 2
    Keywords: brain ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; CELL ; Germany ; MODEL ; MODELS ; VITRO ; SYSTEM ; SITE ; PROTEIN ; ACCUMULATION ; FAMILY ; SIMULATION ; BIOLOGY ; ACID ; TRANSPORT ; EPITHELIAL-CELLS ; organic anion transporters ; NETHERLANDS ; MOUSE MODEL ; specificity ; CHILDREN ; NATURAL-HISTORY ; EFFLUX ; endothelial cells ; TRANSPORTER ; SCIENCE ; blood-brain barrier ; BARRIER ; CAPILLARY ENDOTHELIAL-CELLS ; CELL BIOLOGY ; TRANSPORTERS ; Type ; ACIDEMIA ; COA DEHYDROGENASE-DEFICIENCY ; Dicarboxylic acids ; ENCEPHALOPATHIC CRISES ; Glutaric aciduria type I ; Methylmalonic aciduria ; Organic acid transporter ; Plexus choroideus
    Abstract: Intracerebral accumulation of neurotoxic dicarboxylic acids (DCAs) plays an important pathophysiological role in glutaric aciduria type I and methylmalonic aciduria. Therefore, we investigated the transport characteristics of accumulating DCAs - glutaric (GA), 3-hydroxyglutaric (3-OH-GA) and methylmalonic acid (MMA) - across porcine brain capillary endothelial cells (pBCEC) and human choroid plexus epithelial cells (hCPEC) representing in vitro models of the blood-brain barrier (BBB) and the choroid plexus respectively. We identified expression of organic acid transporters 1 (OAT1) and 3 (OAT3) in pBCEC on mRNA and protein level. For DCAs tested, transport from the basolateral to the apical site (i.e. efflux) was higher than influx. Efflux transport of GA, 3-OH-GA, and MMA across pBCEC was Na+-dependent. ATP-independent, and was inhibited by the OAT substrates para-aminohippuric acid (PAH), estrone sulfate, and taurocholate, and the OAT inhibitor probenecid. Members of the ATP-binding cassette transporter family or the organic anion transporting polypeptide family, namely MRP2, P-gp, BCRP, and OATP1B3, did not mediate transport of GA, 3-OH-GA or MMA confirming the specificity of efflux transport via OATs. In hCPEC, cellular import of GA was dependent on Na+-gradient, inhibited by NaCN, and unaffected by probenecid suggesting a Na+-dependent DCA transporter. Specific transport of GA across hCPEC, however, was not found. In conclusion, our results indicate a low but specific efflux transport for GA, 3-OH-GA, and MMA across pBCEC, an in vitro model of the BBB, via OAT1 and OAT3 but not across hCPEC, an in vitro model of the choroid plexus. (C) 2010 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20302929
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