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dc.contributor.authorBeretta, Matteo
dc.contributor.authorSantos, Celio X.C.
dc.contributor.authorMolenaar, Chris
dc.contributor.authorHafstad, Anne Dragøy
dc.contributor.authorMiller, Chris CJ
dc.contributor.authorRevazian, Aram
dc.contributor.authorBetteridge, Kai
dc.contributor.authorSchröder, Katrin
dc.contributor.authorStreckfuß-Bömeke, Katrin
dc.contributor.authorDoroshow, James H
dc.contributor.authorFleck, Roland A
dc.contributor.authorSu, Tsung-Ping
dc.contributor.authorBelousov, Vsevelod
dc.contributor.authorParsons, Maddy
dc.contributor.authorShah, Ajay M.
dc.date.accessioned2021-01-25T13:09:22Z
dc.date.available2021-01-25T13:09:22Z
dc.date.issued2020-08-10
dc.description.abstractCells subjected to environmental stresses undergo regulated cell death (RCD) when homeostatic programs fail to maintain viability. A major mechanism of RCD is the excessive calcium loading of mitochondria and consequent triggering of the mitochondrial permeability transition (mPT), which is especially important in post‐mitotic cells such as cardiomyocytes and neurons. Here, we show that stress‐induced upregulation of the ROS‐generating protein Nox4 at the ER‐mitochondria contact sites (MAMs) is a pro‐survival mechanism that inhibits calcium transfer through InsP3 receptors (InsP3R). Nox4 mediates redox signaling at the MAM of stressed cells to augment Akt‐dependent phosphorylation of InsP3R, thereby inhibiting calcium flux and mPT‐dependent necrosis. In hearts subjected to ischemia–reperfusion, Nox4 limits infarct size through this mechanism. These results uncover a hitherto unrecognized stress pathway, whereby a ROS‐generating protein mediates pro‐survival effects through spatially confined signaling at the MAM to regulate ER to mitochondria calcium flux and triggering of the mPT.en_US
dc.identifier.citationBeretta, Santos, Molenaar, Hafstad, Miller, Revazian, Betteridge, Schröder, Streckfuß-Bömeke, Doroshow, Fleck, Su, Belousov, Parsons, Shah. Nox4 regulates InsP3 receptor‐dependent Ca2+ release into mitochondria to promote cell survival. EMBO Journal. 2020;39(19)en_US
dc.identifier.cristinIDFRIDAID 1865135
dc.identifier.doi10.15252/embj.2019103530
dc.identifier.issn0261-4189
dc.identifier.issn1460-2075
dc.identifier.urihttps://hdl.handle.net/10037/20472
dc.language.isoengen_US
dc.publisherEMBO Pressen_US
dc.relation.journalEMBO Journal
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2020 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710en_US
dc.titleNox4 regulates InsP3 receptor‐dependent Ca2+ release into mitochondria to promote cell survivalen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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