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  • 1
    Keywords: APOPTOSIS ; CELLS ; SURVIVAL ; Germany ; PATHWAY ; DEATH ; DISEASE ; GENE ; PROTEIN ; METABOLISM ; MICE ; ALZHEIMERS-DISEASE ; ACID ; CELL-SURVIVAL ; MOUSE ; CELL-DEATH ; MUTATION ; MUTATIONS ; XENOPUS ; DIET ; AMYLOID-BETA-PEPTIDE ; neurodegeneration ; 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE-DEFICIENCY ; ERAB ; HSD10 ; organic aciduria
    Abstract: Deficiency of the mitochondrial enzyme 2-methyl-3-hydroxybutyryl-CoA dehydrogenase involved in isoleucine metabolism causes an organic aciduria with atypical neurodegenerative course. The disease-causing gene is HSD17B10 and encodes 17 beta-hydroxysteroid dehydrogenase type 10 (HSD10), a protein also implicated in the pathogenesis of Alzheimer's disease. Here we show that clinical symptoms in patients are not correlated with residual enzymatic activity of mutated HSD10. Loss-of-function and rescue experiments in Xenopus embryos and cells derived from conditional Hsd17b10(-/-) mice demonstrate that a property of HSD10 independent of its enzymatic activity is essential for structural and functional integrity of mitochondria. impairment of this function in neural cells causes apoptotic cell death whilst the enzymatic activity of HSD10 is not required for cell survival. This finding indicates that the symptoms in patients with mutations in the HSD17B10 gene are unrelated to accumulation of toxic metabolites in the isoleucine pathway and, rather, related to defects in general mitochondrial function. Therefore alternative therapeutic approaches to an isoleucine-restricted diet are required
    Type of Publication: Journal article published
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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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  • 3
    Keywords: CELLS ; CELL ; Germany ; PATHWAY ; PATHWAYS ; DEATH ; liver ; ENZYMES ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; METABOLISM ; MICE ; RAT ; hepatocytes ; BIOLOGY ; ENERGY ; BIOSYNTHESIS ; MITOCHONDRIA ; STABILITY ; FAILURE ; DEFICIENT MICE ; RNA-BINDING ; TRANSLATION ; mRNA ; TECHNOLOGY ; HOMEOSTASIS ; HEME ; CELL BIOLOGY ; REGULATORY PROTEINS ; SULFUR CLUSTER BIOGENESIS ; TRANSFERRIN
    Abstract: Mitochondria supply cells with ATP, heme, and iron sulfur clusters (ISC), and mitochondrial energy metabolism involves both heme- and ISC-dependent enzymes. Here, we show that mitochondrial iron supply and function require iron regulatory proteins (IRP), cytosolic RNA-binding proteins that control mRNA translation and stability. Mice lacking both IRP1 and IRP2 in their hepatocytes suffer from mitochondrial iron deficiency and dysfunction associated with alterations of the ISC and heme biosynthetic pathways, leading to liver failure and death. These results uncover a major role of the IRPs in cell biology: to ensure adequate iron supply to the mitochondrion for proper function of this critical organelle
    Type of Publication: Journal article published
    PubMed ID: 20674864
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