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dc.contributor.authorMajd, Homa
dc.contributor.authorKing, Martin S
dc.contributor.authorSmith, Anthony C
dc.contributor.authorKunji, Edmund RS
dc.date.accessioned2018-09-17T13:46:05Z
dc.date.available2018-09-17T13:46:05Z
dc.date.issued2018-01
dc.identifier.issn0005-2728
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/280295
dc.description.abstractMissense mutations of the human mitochondrial citrate carrier, encoded by the SLC25A1 gene, lead to an autosomal recessive neurometabolic disorder characterised by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development, often resulting in early death. Here, we have measured the effect of all twelve known pathogenic mutations on the transport activity. The results show that nine mutations abolish transport of citrate completely, whereas the other three reduce the transport rate by >70%, indicating that impaired citrate transport is the most likely primary cause of the disease. Some mutations may be detrimental to the structure of the carrier, whereas others may impair key functional elements, such as the substrate binding site and the salt bridge network on the matrix side of the carrier. To understand the consequences of impaired citrate transport on metabolism, the substrate specificity was also determined, showing that the human citrate carrier predominantly transports citrate, isocitrate, cis-aconitate, phosphoenolpyruvate and malate. Although D-2- and L-2 hydroxyglutaric aciduria is a metabolic hallmark of the disease, it is unlikely that the citrate carrier plays a significant role in the removal of hydroxyglutarate from the cytosol for oxidation to oxoglutarate in the mitochondrial matrix. In contrast, computer simulations of central metabolism predict that the export of citrate from the mitochondrion cannot be fully compensated by other pathways, restricting the cytosolic production of acetyl-CoA that is required for the synthesis of lipids, sterols, dolichols and ubiquinone, which in turn explains the severe disease phenotypes.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectHumans
dc.subjectBrain Diseases, Metabolic, Inborn
dc.subjectCitric Acid
dc.subjectUbiquinone
dc.subjectSterols
dc.subjectAnion Transport Proteins
dc.subjectOrganic Anion Transporters
dc.subjectMitochondrial Proteins
dc.subjectCatalytic Domain
dc.subjectBiological Transport, Active
dc.subjectMutation, Missense
dc.subjectModels, Biological
dc.subjectComputer Simulation
dc.subjectDolichols
dc.titlePathogenic mutations of the human mitochondrial citrate carrier SLC25A1 lead to impaired citrate export required for lipid, dolichol, ubiquinone and sterol synthesis.
dc.typeArticle
prism.endingPage7
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameBiochim Biophys Acta Bioenerg
prism.startingPage1
prism.volume1859
dc.identifier.doi10.17863/CAM.27663
dcterms.dateAccepted2017-10-09
rioxxterms.versionofrecord10.1016/j.bbabio.2017.10.002
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-01
dc.contributor.orcidKing, Martin [0000-0001-6030-5154]
dc.contributor.orcidSmith, Anthony [0000-0003-0141-0434]
dc.contributor.orcidKunji, Edmund [0000-0002-0610-4500]
dc.identifier.eissn1879-2650
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_U105663139)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/R50564X/1)
pubs.funder-project-idMedical Research Council (MC_UU_00015/1)
pubs.funder-project-idMedical Research Council (MC_U105674181)
cam.issuedOnline2017-10-12
rioxxterms.freetoread.startdate2018-10-12


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International