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dc.contributor.authorAshcroft, Margareten
dc.contributor.authorThomas, LWen
dc.contributor.authorStaples, Oen
dc.contributor.authorTurmaine, Men
dc.date.accessioned2017-05-30T11:22:44Z
dc.date.available2017-05-30T11:22:44Z
dc.date.issued2017-04-27en
dc.identifier.issn2234-943X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/264488
dc.description.abstractHypoxia is a characteristic of the tumor microenvironment and is known to contribute to tumor progression and treatment resistance. Hypoxia-inducible factor (HIF) dimeric transcription factors control the cellular response to reduced oxygenation by regulating the expression of genes involved in metabolic adaptation, cell motility, and survival. Alterations in mitochondrial metabolism are not only a downstream consequence of HIF-signaling but mitochondria reciprocally regulate HIF signaling through multiple means, including oxygen consumption, metabolic intermediates, and reactive oxygen species generation. CHCHD4 is a redox-sensitive mitochondrial protein, which we previously identified and showed to be a novel regulator of HIF and hypoxia responses in tumors. Elevated expression of CHCHD4 in human tumors correlates with the hypoxia gene signature, disease progression, and poor patient survival. Here, we show that either long-term (72 h) exposure to hypoxia (1% O2) or elevated expression of CHCHD4 in tumor cells in normoxia leads to perinuclear accumulation of mitochondria, which is dependent on the expression of HIF-1α. Furthermore, we show that CHCHD4 is required for perinuclear localization of mitochondria and HIF activation in response to long-term hypoxia. Mutation of the functionally important highly conserved cysteines within the Cys-Pro-Cys motif of CHCHD4 or inhibition of complex IV activity (by sodium azide) redistributes mitochondria from the perinuclear region toward the periphery of the cell and blocks HIF activation. Finally, we show that CHCHD4-mediated perinuclear localization of mitochondria is associated with increased intracellular hypoxia within the perinuclear region and constitutive basal HIF activation in normoxia. Our study demonstrates that the intracellular distribution of the mitochondrial network is an important feature of the cellular response to hypoxia, contributing to hypoxic signaling via HIF activation and regulated by way of the cross talk between CHCHD4 and HIF-1α.
dc.description.sponsorshipThe laboratory is funded in part by Cancer Research UK (CR-UK), the Medical Research Council (MRC). LT was funded by MRC grants MR/K002201/1 and MR/K002201/2 and OS was funded by CR-UK grant C7358/A11223.
dc.language.isoenen
dc.publisherFrontiers Media
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjecthypoxiaen
dc.subjecthypoxia-inducible factor-1αen
dc.subjectmitochondriaen
dc.subjectmitochondrial localizationen
dc.subjectperinuclearen
dc.subjectcoiled-coil helix coiled-coil helix domain containing 4en
dc.titleCHCHD4 Regulates Intracellular Oxygenation and Perinuclear Distribution of Mitochondriaen
dc.typeArticle
prism.number71en
prism.publicationDate2017en
prism.publicationNameFrontiers in Oncologyen
prism.volume7en
dc.identifier.doi10.17863/CAM.9966
dcterms.dateAccepted2017-03-28en
rioxxterms.versionofrecord10.3389/fonc.2017.00071en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-04-27en
dc.contributor.orcidAshcroft, Margaret [0000-0002-0066-3707]
dc.identifier.eissn2234-943X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/K002201/2)
pubs.funder-project-idCancer Research UK (19442)
cam.issuedOnline2017-04-27en


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