Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway

Gil-Pitarch, Clàudia; Serrano-Maciá, Marina; Simon, Jorge; Mosca, Laura; Conter, Carolina; Rejano-Gordillo, Claudia M.; Zapata-Pavas, L. Estefanía; Peña-Sanfélix, Patricia; Azkargorta, Mikel; Rodríguez-Agudo, Rubén; Lachiondo-Ortega, Sofía; Mercado-Gómez, María; Delgado, TeresaC.; Porcelli, Marina; Aurrekoetxea, Igor; Sutherland, James D.; Barrio, Rosa; Iruzubieta Coz, Paula; Crespo García, Javier

Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway

Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post...

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Autores:	Gil-Pitarch, Clàudia, Serrano-Maciá, Marina, Simon, Jorge, Mosca, Laura, Conter, Carolina, Rejano-Gordillo, Claudia M., Zapata-Pavas, L. Estefanía, Peña-Sanfélix, Patricia, Azkargorta, Mikel, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofía, Mercado-Gómez, María, Delgado, TeresaC., Porcelli, Marina, Aurrekoetxea, Igor, Sutherland, James D., Barrio, Rosa, Iruzubieta Coz, Paula, Crespo García, Javier
Tipo de recurso:	artículo
Fecha de publicación:	2024
País:	España
Institución:	Universidad de Cantabria (UC)
Repositorio:	UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:	inglés
OAI Identifier:	oai:repositorio.unican.es:10902/34432
Acceso en línea:	https://hdl.handle.net/10902/34432
Access Level:	acceso abierto
Palabra clave:	DILI APAP NEDD8 Mitochondria Necrosis

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network_name_str	España
repository_id_str
dc.title.none.fl_str_mv	Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway
title	Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway
spellingShingle	Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway Gil-Pitarch, Clàudia DILI APAP NEDD8 Mitochondria Necrosis
title_short	Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway
title_full	Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway
title_fullStr	Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway
title_full_unstemmed	Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway
title_sort	Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway
dc.creator.none.fl_str_mv	Gil-Pitarch, Clàudia Serrano-Maciá, Marina Simon, Jorge Mosca, Laura Conter, Carolina Rejano-Gordillo, Claudia M. Zapata-Pavas, L. Estefanía Peña-Sanfélix, Patricia Azkargorta, Mikel Rodríguez-Agudo, Rubén Lachiondo-Ortega, Sofía Mercado-Gómez, María Delgado, TeresaC. Porcelli, Marina Aurrekoetxea, Igor Sutherland, James D. Barrio, Rosa Iruzubieta Coz, Paula Crespo García, Javier
author	Gil-Pitarch, Clàudia
author_facet	Gil-Pitarch, Clàudia Serrano-Maciá, Marina Simon, Jorge Mosca, Laura Conter, Carolina Rejano-Gordillo, Claudia M. Zapata-Pavas, L. Estefanía Peña-Sanfélix, Patricia Azkargorta, Mikel Rodríguez-Agudo, Rubén Lachiondo-Ortega, Sofía Mercado-Gómez, María Delgado, TeresaC. Porcelli, Marina Aurrekoetxea, Igor Sutherland, James D. Barrio, Rosa Iruzubieta Coz, Paula Crespo García, Javier
author_role	author
author2	Serrano-Maciá, Marina Simon, Jorge Mosca, Laura Conter, Carolina Rejano-Gordillo, Claudia M. Zapata-Pavas, L. Estefanía Peña-Sanfélix, Patricia Azkargorta, Mikel Rodríguez-Agudo, Rubén Lachiondo-Ortega, Sofía Mercado-Gómez, María Delgado, TeresaC. Porcelli, Marina Aurrekoetxea, Igor Sutherland, James D. Barrio, Rosa Iruzubieta Coz, Paula Crespo García, Javier
author2_role	author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Universidad de Cantabria
dc.subject.none.fl_str_mv	DILI APAP NEDD8 Mitochondria Necrosis
topic	DILI APAP NEDD8 Mitochondria Necrosis
description	Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.
publishDate	2024
dc.date.none.fl_str_mv	2024 2024-01-01
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 NA http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/10902/34432
url	https://hdl.handle.net/10902/34432
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.publisher.none.fl_str_mv	Cell Press Elsevier
publisher.none.fl_str_mv	Cell Press Elsevier
dc.source.none.fl_str_mv	Cell Reports Medicine, 2024, 5, 101653 reponame:UCrea Repositorio Abierto de la Universidad de Cantabria instname:Universidad de Cantabria (UC)
instname_str	Universidad de Cantabria (UC)
reponame_str	UCrea Repositorio Abierto de la Universidad de Cantabria
collection	UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_	1869413577183461376
spelling	Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathwayGil-Pitarch, ClàudiaSerrano-Maciá, MarinaSimon, JorgeMosca, LauraConter, CarolinaRejano-Gordillo, Claudia M.Zapata-Pavas, L. EstefaníaPeña-Sanfélix, PatriciaAzkargorta, MikelRodríguez-Agudo, RubénLachiondo-Ortega, SofíaMercado-Gómez, MaríaDelgado, TeresaC.Porcelli, MarinaAurrekoetxea, IgorSutherland, James D.Barrio, RosaIruzubieta Coz, PaulaCrespo García, JavierDILIAPAPNEDD8MitochondriaNecrosisDrug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.Acknowledgments: This work was supported by grants from Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00 CEX2021-001136-S integrado en el Plan Estatal de Investigación Científica y Técnica e Innovación, cofinanciado con Fondos FEDER (for M.L.M.-C.); Ministerio de Ciencia e Innovación, Programa Retos-Colaboración RTC2019-007125-1 (for M.L.M.-C.); Instituto de Salud Carlos III, Proyectos Investigación en Salud DTS20/00138 (for M.L.M.-C.); La Caixa Scientific Foundation (HR17-00601) (for M.L.M.-C.); La Caixa Consortium (for M.L.M.-C.); Ayudas Fundación Científica AECC para proyectos coordinados (IGTP-AECC_2022-042) (for M.L.M.-C.); Transferencia tecnológica 2022 (6/12/TT/2022/00001) (for M.L.M.-C.); Desarrollo Tecnológico en Salud (DTS20/00138) (for M.L.M.-C.); Ayudas a proyectos de investigación y desarrollo en salud (2023333041) (for M.L.M.-C.); Health Research 2017 (HR17-00601) (for M.L.M.-C.); Caixa Impulse Innovation 2023 (CI23-20155) (for M.L.M.-C.); PhD fellowship from AECC (PRDVZ172010SERR) awarded to M.S.-M.; FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación PID2021-126096NB-I00 and RED2018-102379-T; and Xunta de Galicia 2021-CP085 and 2020-PG0157 to R.N. This work was supported by a PhD fellowship from MINECO (REF BES-2017-080435) awarded to I.G.-R., PRE2019-088771 awarded to C.G.-P.; C.M.R.-G. was supported by a postdoctoral contract Margarita Salas (University of Extremadura) from the Program of Requalification of the Spanish University System (Spanish Ministry of Universities) financed by the European Union – NextGenerationEU; PRE2018-084840 awarded to M.M.-G.; PRE2021-097073 awarded to P.P.-S., by Spanish Ministerio de Ciencia e Innovación (MICINN); PRDVZ233980ZAPA awarded to L.E.Z.-P. by Ayudas Predoctorales AECC Bizkaia 2023; grants BFU2010-17857 and PID2019-109055RB-I00, Spanish Ministry of Economy and Competitiveness grants BFU2013-47531-R and BFU2016-77408-R, and also by 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.; MCIN/AEI/10.13039/501100011033 (PID2021-124425OB-I00 to P.A.) co-financed by the European Regional Development Fund (ERDF); and Grupos consolidados Gobierno Vasco IT1476-22 to P.A. We would like to acknowledge Begoña Rodríguez Iruretagoyena for her technical support.Cell Press ElsevierUniversidad de Cantabria20242024-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/34432Cell Reports Medicine, 2024, 5, 101653reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/344322026-06-02T12:39:31Z
score	15,811543

Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway

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