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

dc.contributor.authorGonzález Recio, Irene
dc.contributor.authorSimón Espinosa, Jorge
dc.contributor.authorGoikoetxea Usandizaga, Naroa
dc.contributor.authorSerrano Maciá, Marina
dc.contributor.authorMercado Gómez, María
dc.contributor.authorRodríguez Agudo, Rubén
dc.contributor.authorLachiondo Ortega, Sofía
dc.contributor.authorGil Pitarch, Clàudia
dc.contributor.authorFernández Rodríguez, Carmen
dc.contributor.authorCastellana, Donatello
dc.contributor.authorLatasa, María Ujué
dc.contributor.authorAbecia Aliende, Leticia ORCID
dc.contributor.authorAnguita Castillo, Juan de Dios
dc.contributor.authorDelgado, Teresa C.
dc.contributor.authorIruzubieta, Paula
dc.contributor.authorCrespo, Javier
dc.contributor.authorHardy, Serge
dc.contributor.authorPetrov, Petar D.
dc.contributor.authorJover, Ramiro
dc.contributor.authorÁvila, Matías A. ORCID
dc.contributor.authorMartín Plágaro, César Augusto
dc.contributor.authorSchaeper, Ute
dc.contributor.authorTremblay, Michel L.
dc.contributor.authorDear, James W.
dc.contributor.authorMasson, Steven
dc.contributor.authorMcCain, Misti Vanette
dc.contributor.authorReeves, Helen L.
dc.contributor.authorAndrade, Raúl
dc.contributor.authorLucena, M. Isabel
dc.contributor.authorBuccella, Daniela
dc.contributor.authorMartínez de la Cruz, Alfonso
dc.contributor.authorMartínez Chantar, María Luz ORCID
dc.date.accessioned2023-01-25T17:17:01Z
dc.date.available2023-01-25T17:17:01Z
dc.date.issued2022-11
dc.identifier.citationNature Communications 13(1) : (2022) // Article ID 6816es_ES
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10810/59482
dc.description.abstractDrug induced liver injury (DILI) is an important cause acute liver failure. Here the authors report that serum Mg2+ serum levels decrease in patients with DILI as well as in preclinical animal models treated with acetaminophen overdose, and that early intervention targeting the Mg2+ transporter Cyclin M4 may be beneficial for acetaminophen overdose in preclinical models. Acetaminophen 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.sponsorshipThis 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 LAM-C); 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 thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644) and PhD fellowship from MINECO (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.language.isoenges_ES
dc.publisherNaturees_ES
dc.relationinfo:eu-repo/grantAgreement/MICINN/PID2020-117116RB-I00es_ES
dc.relationinfo:eu-repo/grantAgreement/MICINN/PID2019-109055RB-100es_ES
dc.relationinfo:eu-repo/grantAgreement/MICINN/RYC2020-029316-Ies_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/SEV-2016-0644es_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.subjectintracellular Magnesiumes_ES
dc.subjectn-acetylcysteinees_ES
dc.subjecthepatotoxicityes_ES
dc.subjectmitochondriales_ES
dc.subjectinhibitiones_ES
dc.subjectCalciumes_ES
dc.subjectMg2+es_ES
dc.subjectmicees_ES
dc.subjectthapsigargines_ES
dc.subjectinflammationes_ES
dc.titleRestoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damagees_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holder© The Author(s) 2022. his article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.es_ES
dc.rights.holderAtribución 3.0 España*
dc.relation.publisherversionhttps://www.nature.com/articles/s41467-022-34262-0es_ES
dc.identifier.doi10.1038/s41467-022-34262-0
dc.departamentoesBioquímica y biología moleculares_ES
dc.departamentoesInmunología, microbiología y parasitologíaes_ES
dc.departamentoeuBiokimika eta biologia molekularraes_ES
dc.departamentoeuImmunologia, mikrobiologia eta parasitologiaes_ES


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© The Author(s) 2022. his article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
Except where otherwise noted, this item's license is described as © The Author(s) 2022. his article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.