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Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation.

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cam.issuedOnline2018-03-29
cam.orpheus.successThu Jan 30 12:58:24 GMT 2020 - The item has an open VoR version.
dc.contributor.authorFazakerley, Daniel J
dc.contributor.authorMinard, Annabel Y
dc.contributor.authorKrycer, James R
dc.contributor.authorThomas, Kristen C
dc.contributor.authorStöckli, Jacqueline
dc.contributor.authorHarney, Dylan J
dc.contributor.authorBurchfield, James G
dc.contributor.authorMaghzal, Ghassan J
dc.contributor.authorCaldwell, Stuart T
dc.contributor.authorHartley, Richard C
dc.contributor.authorStocker, Roland
dc.contributor.authorMurphy, Michael P
dc.contributor.authorJames, David E
dc.contributor.orcidFazakerley, Daniel [0000-0001-8241-2903]
dc.contributor.orcidMurphy, Mike [0000-0003-1115-9618]
dc.date.accessioned2018-06-28T13:41:50Z
dc.date.available2018-06-28T13:41:50Z
dc.date.issued2018-05-11
dc.description.abstractMitochondrial oxidative stress, mitochondrial dysfunction, or both have been implicated in insulin resistance. However, disentangling the individual roles of these processes in insulin resistance has been difficult because they often occur in tandem, and tools that selectively increase oxidant production without impairing mitochondrial respiration have been lacking. Using the dimer/monomer status of peroxiredoxin isoforms as an indicator of compartmental hydrogen peroxide burden, we provide evidence that oxidative stress is localized to mitochondria in insulin-resistant 3T3-L1 adipocytes and adipose tissue from mice. To dissociate oxidative stress from impaired oxidative phosphorylation and study whether mitochondrial oxidative stress per se can cause insulin resistance, we used mitochondria-targeted paraquat (MitoPQ) to generate superoxide within mitochondria without directly disrupting the respiratory chain. At ≤10 μm, MitoPQ specifically increased mitochondrial superoxide and hydrogen peroxide without altering mitochondrial respiration in intact cells. Under these conditions, MitoPQ impaired insulin-stimulated glucose uptake and glucose transporter 4 (GLUT4) translocation to the plasma membrane in both adipocytes and myotubes. MitoPQ recapitulated many features of insulin resistance found in other experimental models, including increased oxidants in mitochondria but not cytosol; a more profound effect on glucose transport than on other insulin-regulated processes, such as protein synthesis and lipolysis; an absence of overt defects in insulin signaling; and defective insulin- but not AMP-activated protein kinase (AMPK)-regulated GLUT4 translocation. We conclude that elevated mitochondrial oxidants rapidly impair insulin-regulated GLUT4 translocation and significantly contribute to insulin resistance and that MitoPQ is an ideal tool for studying the link between mitochondrial oxidative stress and regulated GLUT4 trafficking.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.24942
dc.identifier.eissn1083-351X
dc.identifier.issn0021-9258
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/277619
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1074/jbc.ra117.001254
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMitochondrial dysfunction
dc.subjectadipocyte
dc.subjectadipose tissue
dc.subjecthydrogen peroxide
dc.subjectinsulin
dc.subjectinsulin resistance
dc.subjectmitochondria
dc.subjectmuscle
dc.subjectoxidative stress
dc.subjectsuperoxide ion
dc.subject3T3-L1 Cells
dc.subjectAdenylate Kinase
dc.subjectAdipocytes
dc.subjectAnimals
dc.subjectElectron Transport
dc.subjectGlucose
dc.subjectGlucose Transporter Type 4
dc.subjectHerbicides
dc.subjectHydrogen Peroxide
dc.subjectInsulin
dc.subjectInsulin Resistance
dc.subjectMale
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMitochondria
dc.subjectMyoblasts
dc.subjectOxidative Phosphorylation
dc.subjectOxygen Consumption
dc.subjectParaquat
dc.subjectPeroxiredoxins
dc.subjectProtein Isoforms
dc.subjectSuperoxides
dc.titleMitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation.
dc.typeArticle
dcterms.dateAccepted2018-03-30
prism.endingPage7328
prism.issueIdentifier19
prism.publicationDate2018
prism.publicationNameJ Biol Chem
prism.startingPage7315
prism.volume293
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_U105663142)
rioxxterms.licenseref.startdate2018-05
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1074/jbc.RA117.001254

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