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APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS.

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cam.issuedOnline2018-12-14
dc.contributor.authorSignes, Alba
dc.contributor.authorCerutti, Raffaele
dc.contributor.authorDickson, Anna S
dc.contributor.authorBenincá, Cristiane
dc.contributor.authorHinchy, Elizabeth C
dc.contributor.authorGhezzi, Daniele
dc.contributor.authorCarrozzo, Rosalba
dc.contributor.authorBertini, Enrico
dc.contributor.authorMurphy, Michael P
dc.contributor.authorNathan, James A
dc.contributor.authorViscomi, Carlo
dc.contributor.authorFernandez-Vizarra, Erika
dc.contributor.authorZeviani, Massimo
dc.contributor.orcidGhezzi, Daniele [0000-0002-9358-1566]
dc.contributor.orcidBertini, Enrico [0000-0001-9276-4590]
dc.contributor.orcidNathan, James A [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.date.accessioned2018-12-22T00:31:25Z
dc.date.available2018-12-22T00:31:25Z
dc.date.issued2019-01
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.identifier.doi10.17863/CAM.34706
dc.identifier.eissn1757-4684
dc.identifier.issn1757-4676
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287402
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.15252/emmm.201809582
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAPOPT1‐COA8
dc.subjectcytochrome c oxidase
dc.subjectmitochondrial encephalopathy
dc.subjectproteasome–ubiquitin system
dc.subjectreactive oxygen species
dc.subjectAnimals
dc.subjectApoptosis Regulatory Proteins
dc.subjectCells, Cultured
dc.subjectElectron Transport Complex IV
dc.subjectGenetic Complementation Test
dc.subjectHumans
dc.subjectMice
dc.subjectMice, Knockout
dc.subjectMitochondrial Proteins
dc.subjectProtein Multimerization
dc.subjectReactive Oxygen Species
dc.subjectUnfolded Protein Response
dc.titleAPOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS.
dc.typeArticle
dcterms.dateAccepted2018-11-21
prism.issueIdentifier1
prism.publicationDate2019
prism.publicationNameEMBO Mol Med
prism.volume11
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)
pubs.funder-project-idMedical Research Council (MC_UU_00015/7)
rioxxterms.licenseref.startdate2019-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.15252/emmm.201809582

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