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Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage

dc.contributor.authorGonzález-Recio, Irenees_ES
dc.contributor.authorSimón, Jorgees_ES
dc.contributor.authorGoikoetxea-Usandizaga, Naroaes_ES
dc.contributor.authorSerrano-Maciá, Marinaes_ES
dc.contributor.authorMercado-Gómez, Mariaes_ES
dc.contributor.authorRodríguez-Agudo, Rubénes_ES
dc.contributor.authorLachiondo-Ortega, Sofíaes_ES
dc.contributor.authorGil-Pitarch, Clàudiaes_ES
dc.contributor.authorFernández-Rodríguez, Carmenes_ES
dc.contributor.authorCastellana, Donatelloes_ES
dc.contributor.authorLatasa, Maria Ues_ES
dc.contributor.authorAbecia, Leticiaes_ES
dc.contributor.authorAnguita, Juanes_ES
dc.contributor.authorDelgado, Teresa Ces_ES
dc.contributor.authorIruzubieta, Paulaes_ES
dc.contributor.authorCrespo García, Javier es_ES
dc.contributor.authorHardy, Sergees_ES
dc.contributor.authorPetrov, Petar Des_ES
dc.contributor.authorJover, Ramiroes_ES
dc.contributor.authorAvila, Matías Aes_ES
dc.contributor.otherUniversidad de Cantabriaes_ES
dc.date.accessioned2023-01-17T16:23:31Z
dc.date.available2023-01-17T16:23:31Z
dc.date.issued2022es_ES
dc.identifier.issn2041-1723es_ES
dc.identifier.otherPID2020-117116RB-I00es_ES
dc.identifier.otherBFU2013- 47531-R ; BFU2016-77408-R ; PID2019-109055RB-100es_ES
dc.identifier.urihttps://hdl.handle.net/10902/27272
dc.description.abstractAcetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury.es_ES
dc.description.sponsorshipAcknowledgements: This work was supported by Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00 integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación, cofinanciado con Fondos FEDER (to MLM-C), Ministerio de Ciencia e Innovación CONSOLIDER-INGENIO 2010 Program Grant CSD2008-00005 (to LAMC); Spanish Ministry of Economy and Competitiveness Grant BFU2013-47531-R, BFU2016-77408-R, PID2019-109055RB-100 (to L.A.M.-C.) (MINECO/FEDER, UE); Asociación Española contra el Cáncer (MLM-C, TC-D), Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M.-C.), La Caixa Foundation Program (to M.L.M.-C.), Fundacion BBVA UMBRELLA project (to M.L.M.-C.), Ayuda RYC2020-029316-I financiada por MICIN/AEI/10.13039/501100011033 (to TC-D), Plataforma de Investigación Clínica-SCReN (PT17 0017 0020) (to M.I.-L.), programa retos RTC2019-007125-1 (to M.L.M.-C, J.S.), Proyectos Investigacion en Salud DTS20/00138 (to M.L.M.-C., J.S), ERA-Net E-Rare EJP RD Joint Translational Call for Rare Diseases FIGHT-CNNM2 (EJPRD19-040) and from Instituto Carlos III, Spain (REF G95229142) (to L.A.M.-C.), US National Institutes of Health under grant CA217817 (to D.B.), Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thankMINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644) and PhD fellowship fromMINECO (REF BES-2017-080435) awarded to I.G.-R. The collection and storage of patients tissues was supported by the Newcastle Biomedicine Biobank and the European Community’s Seventh Framework Programme (FP7/2001–2013) and Cancer Research UK awards Cancer Research UK grants C18342/A23390; C9380/A18084 and C9380/A26813. Finally, we would like to acknowledge Begoña Rodríguez Iruretagoyena for the technical support provided.es_ES
dc.format.extent21 p.es_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Groupes_ES
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.sourceNature Communications, 2022, 13(1), 6816es_ES
dc.titleRestoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damagees_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.relation.publisherVersionhttps://doi.org/10.1038/s41467-022-34262-0es_ES
dc.rights.accessRightsopenAccesses_ES
dc.identifier.DOI10.1038/s41467-022-34262-0es_ES
dc.type.versionpublishedVersiones_ES


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