Show simple item record

dc.contributor.authorReyes, Aurelio
dc.contributor.authorMelchionda, Laura
dc.contributor.authorBurlina, Alberto
dc.contributor.authorRobinson, Alan J
dc.contributor.authorGhezzi, Daniele
dc.contributor.authorZeviani, Massimo
dc.date.accessioned2018-11-17T00:32:01Z
dc.date.available2018-11-17T00:32:01Z
dc.date.issued2018-10
dc.identifier.issn1757-4676
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285390
dc.description.abstractTIMM50 is an essential component of the TIM23 complex, the mitochondrial inner membrane machinery that imports cytosolic proteins containing a mitochondrial targeting presequence into the mitochondrial inner compartment. Whole exome sequencing (WES) identified compound heterozygous pathogenic mutations in TIMM50 in an infant patient with rapidly progressive, severe encephalopathy. Patient fibroblasts presented low levels of TIMM50 and other components of the TIM23 complex, lower mitochondrial membrane potential, and impaired TIM23-dependent protein import. As a consequence, steady-state levels of several components of mitochondrial respiratory chain were decreased, resulting in decreased respiration and increased ROS production. Growth of patient fibroblasts in galactose shifted energy production metabolism toward oxidative phosphorylation (OxPhos), producing an apparent improvement in most of the above features but also increased apoptosis. Complementation of patient fibroblasts with TIMM50 improved or restored these features to control levels. Moreover, RNASEH1 and ISCU mutant fibroblasts only shared a few of these features with TIMM50 mutant fibroblasts. Our results indicate that mutations in TIMM50 cause multiple mitochondrial bioenergetic dysfunction and that functional TIMM50 is essential for cell survival in OxPhos-dependent conditions.
dc.format.mediumPrint
dc.languageeng
dc.publisherEMBO
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCells, Cultured
dc.subjectFibroblasts
dc.subjectHumans
dc.subjectBrain Diseases
dc.subjectMitochondrial Diseases
dc.subjectMembrane Transport Proteins
dc.subjectGenetic Complementation Test
dc.subjectCell Survival
dc.subjectOxidative Phosphorylation
dc.subjectMutation
dc.subjectInfant
dc.subjectItaly
dc.subjectFemale
dc.titleMutations in TIMM50 compromise cell survival in OxPhos-dependent metabolic conditions.
dc.typeArticle
prism.issueIdentifier10
prism.publicationDate2018
prism.publicationNameEMBO Mol Med
prism.volume10
dc.identifier.doi10.17863/CAM.32756
dcterms.dateAccepted2018-08-14
rioxxterms.versionofrecord10.15252/emmm.201708698
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-10
dc.contributor.orcidReyes, Aurelio [0000-0003-2876-2202]
dc.contributor.orcidGhezzi, Daniele [0000-0002-9358-1566]
dc.contributor.orcidZeviani, Massimo [0000-0002-9067-5508]
dc.identifier.eissn1757-4684
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_UP_1002/1)
pubs.funder-project-idEuropean Research Council (322424)
pubs.funder-project-idMedical Research Council (MC_UU_00015/8)
pubs.funder-project-idMRC (MC_UU_00015/8)
pubs.funder-project-idMedical Research Council (MC_U105674181)
cam.issuedOnline2018-09-06


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

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