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dc.contributor.authorHe, Jayen
dc.contributor.authorFord, HCen
dc.contributor.authorCarroll, Josephen
dc.contributor.authorDing, Sen
dc.contributor.authorFearnley, Ianen
dc.contributor.authorWalker, Johnen
dc.date.accessioned2018-04-11T14:02:45Z
dc.date.available2018-04-11T14:02:45Z
dc.date.issued2017-03-28en
dc.identifier.issn0027-8424
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/274781
dc.description.abstractThe permeability transition in human mitochondria refers to the opening of a nonspecific channel, known as the permeability transition pore (PTP), in the inner membrane. Opening can be triggered by calcium ions, leading to swelling of the organelle, disruption of the inner membrane, and ATP synthesis, followed by cell death. Recent proposals suggest that the pore is associated with the ATP synthase complex and specifically with the ring of c-subunits that constitute the membrane domain of the enzyme's rotor. The c-subunit is produced from three nuclear genes, ATP5G1, ATP5G2, and ATP5G3, encoding identical copies of the mature protein with different mitochondrial-targeting sequences that are removed during their import into the organelle. To investigate the involvement of the c-subunit in the PTP, we generated a clonal cell, HAP1-A12, from near-haploid human cells, in which ATP5G1, ATP5G2, and ATP5G3 were disrupted. The HAP1-A12 cells are incapable of producing the c-subunit, but they preserve the characteristic properties of the PTP. Therefore, the c-subunit does not provide the PTP. The mitochondria in HAP1-A12 cells assemble a vestigial ATP synthase, with intact F1-catalytic and peripheral stalk domains and the supernumerary subunits e, f, and g, but lacking membrane subunits ATP6 and ATP8. The same vestigial complex plus associated c-subunits was characterized from human 143B ρ(0) cells, which cannot make the subunits ATP6 and ATP8, but retain the PTP. Therefore, none of the membrane subunits of the ATP synthase that are involved directly in transmembrane proton translocation is involved in forming the PTP.
dc.description.sponsorshipThis work was supported by the Medical Research Council (MRC) of the United Kingdom by Grant MC_U1065663150 and by Programme Grant MR/M009858/1 (to J.E.W.). H.C.F. received an MRC PhD studentship.
dc.languageengen
dc.publisherNational Academy of Sciences
dc.subjectATP synthaseen
dc.subjectATP5Gen
dc.subjecthuman mitochondriaen
dc.subjectpermeability transition poreen
dc.subjectsubunit cen
dc.titlePersistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase.en
dc.typeArticle
prism.endingPage3414
prism.issueIdentifier13en
prism.publicationDate2017en
prism.publicationNameProceedings of the National Academy of Sciencesen
prism.startingPage3409
prism.volume114en
dc.identifier.doi10.17863/CAM.21923
dcterms.dateAccepted2017-02-17en
rioxxterms.versionofrecord10.1073/pnas.1702357114en
rioxxterms.versionAM*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-03-28en
dc.contributor.orcidWalker, John [0000-0001-7929-2162]
dc.identifier.eissn1091-6490
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_EX_MR/M009858/1)
pubs.funder-project-idMRC (MC_U105663150)
pubs.funder-project-idMRC (MC_UU_00015/8)
pubs.funder-project-idMRC (MC_UU_00015/8)


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