Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics

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• dc.contributor.author Carreras Sureda, Amado, 1986-
• dc.contributor.author Vicente García, Rubén, 1978-
• dc.contributor.author Hetz, Claudio
• dc.date.accessioned 2023-04-27T06:09:12Z
• dc.date.available 2023-04-27T06:09:12Z
• dc.date.issued 2019
• dc.description.abstract Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics.
• dc.description.sponsorship This work was funded by FONDECYT 1140549, FONDAP program 15150012, the Millennium Institute P09-015-F and the European Commission R&D MSCA-RISE 734749 (to C.H.); the Michael J. Fox Foundation for Parkinson’s Research target validation grant number 9277, FONDEF ID16I10223, FONDEF D11E1007, US Office of Naval Research-Global N62909-16-1-2003, US Air Force Office of Scientific Research FA9550-16-1-0384, ALSRP Therapeutic Idea Award AL150111, Muscular Dystrophy Association 382453, Seed grant Leading House for the Latin American Region, Switzerland and CONICYT-Brazil 441921/2016-7 (to C.H.), FONDECYT 1160332 and FONDAP15150012 (to J.C.C.); the Spanish Ministry of Economy and Competitiveness SAF2014-52228-R, Unidad de Excelencia María de Maeztu, funded by the MINECO (ref: MDM-2014-0370) and Fundació la Marató de TV3 20134030 (to R.V.); NIH NS095892 (to R.L.W.); FONDECYT 11180825 (to H.U.); FONDECYT 3150113 and EMBO ASTF 385-2016 (to A.C.-S.); FONDECYT 3140355 (to E.R.-F.); FONDECYT 3140458 and 11170291 (to F.J.); FONDECYT 3180427 (to Y.H.); FONDECYT 3190738 (to A.S.-C.); FONDECYT 11170546 and CONICYT PAI 77170091 (to C.T.-R.); R01DK113171, R01CA198103 and R01DK103185 (to R.J.K.); FONDECYT 1150766 (to F.A.C.); the Research Council KU Leuven grant OT14/101 (to G.B.); the Research Foundation – Flanders (FWO) G.0C91.14N, G.0A34.16N and the FWO Scientific Research Community “Ca2+ signaling in health, disease and therapy” W0.019.17 (to G.B.); FWO (G049817N, G076617N) and KU Leuven (C16/15/073) (to P.A.); a FWO doctorate fellowship (to M.K.); the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant 675448 (to M.L.S.); CONICYT fellowship PCHA/Doctorado Nacional/2016-21160232 (to M.G.-Q.); the George E. Hewitt Foundation for a postdoctoral fellowship (to D.E.M.); Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche – Projets blancs; under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale; a donation from Elior; the European Research Area Network on Cardiovascular Diseases (MINOTAUR), Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085); Institut National du Cancer; Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination; and the SIRIC Cancer Research and Personalized Medicine (to G.K.).
• dc.format.mimetype application/pdf
• dc.identifier.citation Carreras-Sureda A, Jaña F, Urra H, Durand S, Mortenson DE, Sagredo A et al. Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics. Nat Cell Biol. 2019;21(6):755-67. DOI: 10.1038/s41556-019-0329-y
• dc.identifier.doi http://dx.doi.org/10.1038/s41556-019-0329-y
• dc.identifier.issn 1465-7392
• dc.identifier.uri http://hdl.handle.net/10230/56581
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Cell Biol. 2019;21(6):755-67
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-52228-R
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/675448
• dc.rights © Springer Nature Publishing AG Carreras-Sureda A, Jaña F, Urra H, Durand S, Mortenson DE, Sagredo A et al. Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics. Nat Cell Biol. 2019;21(6):755-67 [http://dx.doi.org/10.1038/s41556-019-0329-y]
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Calcium signalling
• dc.subject.keyword Endoplasmic reticulum
• dc.subject.keyword Energy metabolism
• dc.title Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion