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dc.contributor.authorRobb, Ellen L
dc.contributor.authorHall, Andrew R
dc.contributor.authorPrime, Tracy A
dc.contributor.authorEaton, Simon
dc.contributor.authorSzibor, Marten
dc.contributor.authorViscomi, Carlo
dc.contributor.authorJames, Andrew
dc.contributor.authorMurphy, Mike
dc.date.accessioned2018-12-18T00:33:24Z
dc.date.available2018-12-18T00:33:24Z
dc.date.issued2018-06-22
dc.identifier.issn0021-9258
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287131
dc.description.abstractThe generation of mitochondrial superoxide (O2̇̄) by reverse electron transport (RET) at complex I causes oxidative damage in pathologies such as ischemia reperfusion injury, but also provides the precursor to H2O2 production in physiological mitochondrial redox signaling. Here, we quantified the factors that determine mitochondrial O2̇̄ production by RET in isolated heart mitochondria. Measuring mitochondrial H2O2 production at a range of proton-motive force (Δp) values and for several coenzyme Q (CoQ) and NADH pool redox states obtained with the uncoupler p-trifluoromethoxyphenylhydrazone, we show that O2̇̄ production by RET responds to changes in O2 concentration, the magnitude of Δp, and the redox states of the CoQ and NADH pools. Moreover, we determined how expressing the alternative oxidase from the tunicate Ciona intestinalis to oxidize the CoQ pool affected RET-mediated O2̇̄ production at complex I, underscoring the importance of the CoQ pool for mitochondrial O2̇̄ production by RET. An analysis of O2̇̄ production at complex I as a function of the thermodynamic forces driving RET at complex I revealed that many molecules that affect mitochondrial reactive oxygen species production do so by altering the overall thermodynamic driving forces of RET, rather than by directly acting on complex I. These findings clarify the factors controlling RET-mediated mitochondrial O2̇̄ production in both pathological and physiological conditions. We conclude that O2̇̄ production by RET is highly responsive to small changes in Δp and the CoQ redox state, indicating that complex I RET represents a major mode of mitochondrial redox signaling.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMitochondria, Heart
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice
dc.subjectRats
dc.subjectRats, Wistar
dc.subjectHydrogen Peroxide
dc.subjectSuperoxides
dc.subjectUbiquinone
dc.subjectElectron Transport Complex I
dc.subjectSignal Transduction
dc.subjectElectron Transport
dc.subjectOxidative Phosphorylation
dc.subjectFemale
dc.subjectMale
dc.titleControl of mitochondrial superoxide production by reverse electron transport at complex I.
dc.typeArticle
prism.endingPage9879
prism.issueIdentifier25
prism.publicationDate2018
prism.publicationNameJ Biol Chem
prism.startingPage9869
prism.volume293
dc.identifier.doi10.17863/CAM.34440
rioxxterms.versionofrecord10.1074/jbc.RA118.003647
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-06
dc.contributor.orcidViscomi, Carlo [0000-0001-6050-0566]
dc.contributor.orcidMurphy, Mike [0000-0003-1115-9618]
dc.identifier.eissn1083-351X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_UU_00015/3)
pubs.funder-project-idWellcome Trust (110159/Z/15/Z)
pubs.funder-project-idMedical Research Council (MC_UP_1002/1)
pubs.funder-project-idMRC (MC_UP_1002/1)
pubs.funder-project-idMedical Research Council (MC_U105663142)
pubs.funder-project-idMedical Research Council (MC_UU_00015/8)
pubs.funder-project-idMRC (MC_UU_00015/8)
rioxxterms.freetoread.startdate2019-12-17


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