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dc.contributor.authorSignes, Alba
dc.contributor.authorCerutti, Raffaele
dc.contributor.authorDickson, Anna
dc.contributor.authorBenincá, Cristiane
dc.contributor.authorHinchy, Elizabeth C
dc.contributor.authorGhezzi, Daniele
dc.contributor.authorCarrozzo, Rosalba
dc.contributor.authorBertini, Enrico
dc.contributor.authorMurphy, Mike
dc.contributor.authorNathan, James
dc.contributor.authorViscomi, Carlo
dc.contributor.authorFernandez-Vizarra, Erika
dc.contributor.authorZeviani, Massimo
dc.date.accessioned2018-12-22T00:31:25Z
dc.date.available2018-12-22T00:31:25Z
dc.date.issued2019-01
dc.identifier.issn1757-4676
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287402
dc.description.abstractLoss-of-function mutations in APOPT1, a gene exclusively found in higher eukaryotes, cause a characteristic type of cavitating leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency. Although the genetic association of APOPT1 pathogenic variants with isolated COX defects is now clear, the biochemical link between APOPT1 function and COX has remained elusive. We investigated the molecular role of APOPT1 using different approaches. First, we generated an Apopt1 knockout mouse model which shows impaired motor skills, e.g., decreased motor coordination and endurance, associated with reduced COX activity and levels in multiple tissues. In addition, by achieving stable expression of wild-type APOPT1 in control and patient-derived cultured cells we ruled out a role of this protein in apoptosis and established instead that this protein is necessary for proper COX assembly and function. On the other hand, APOPT1 steady-state levels were shown to be controlled by the ubiquitination-proteasome system (UPS). Conversely, in conditions of increased oxidative stress, APOPT1 is stabilized, increasing its mature intramitochondrial form and thereby protecting COX from oxidatively induced degradation.
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.subjectAnimals
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjectReactive Oxygen Species
dc.subjectElectron Transport Complex IV
dc.subjectMitochondrial Proteins
dc.subjectGenetic Complementation Test
dc.subjectApoptosis Regulatory Proteins
dc.subjectProtein Multimerization
dc.subjectUnfolded Protein Response
dc.titleAPOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS.
dc.typeArticle
prism.issueIdentifier1
prism.publicationDate2019
prism.publicationNameEMBO Mol Med
prism.volume11
dc.identifier.doi10.17863/CAM.34706
dcterms.dateAccepted2018-11-21
rioxxterms.versionofrecord10.15252/emmm.201809582
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-01
dc.contributor.orcidDickson, Anna [0000-0001-6431-586X]
dc.contributor.orcidGhezzi, Daniele [0000-0002-9358-1566]
dc.contributor.orcidBertini, Enrico [0000-0001-9276-4590]
dc.contributor.orcidMurphy, Mike [0000-0003-1115-9618]
dc.contributor.orcidNathan, James [0000-0002-0248-1632]
dc.contributor.orcidViscomi, Carlo [0000-0001-6050-0566]
dc.contributor.orcidFernandez-Vizarra, Erika [0000-0002-2469-142X]
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-idWellcome Trust (102770/Z/13/Z)
pubs.funder-project-idLister Institute of Preventive Medicine (unknown)
pubs.funder-project-idMedical Research Council (MC_UU_00015/3)
pubs.funder-project-idWellcome Trust (110159/Z/15/Z)
pubs.funder-project-idMRC (MC_UP_1002/1)
pubs.funder-project-idMedical Research Council (MC_UU_00015/8)
pubs.funder-project-idEuropean Research Council (322424)
pubs.funder-project-idMRC (MC_UU_00015/8)
cam.issuedOnline2018-12-14


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