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...
| Autores: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Tipo de documento: | Artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Cantabria (UC) |
| Repositorio: | UCrea Repositorio Abierto de la Universidad de Cantabria |
| Lenguaje: | Inglés |
| OAI Identifier: | oai:repositorio.unican.es:10902/34432 |
| Acceso en línea: | https://hdl.handle.net/10902/34432 |
| Nivel de acceso: | Acceso abierto |
| Palabra clave: | DILI APAP NEDD8 Mitochondria Necrosis |
| _version_ | 1878736681434087424 |
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| author | Gil-Pitarch, Clàudia |
| 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 |
| author_browse | Aurrekoetxea, Igor Azkargorta, Mikel Barrio, Rosa Conter, Carolina Crespo García, Javier Delgado, TeresaC. Gil-Pitarch, Clàudia Iruzubieta Coz, Paula Lachiondo-Ortega, Sofía Mercado-Gómez, María Mosca, Laura Peña-Sanfélix, Patricia Porcelli, Marina Rejano-Gordillo, Claudia M. Rodríguez-Agudo, Rubén Serrano-Maciá, Marina Simon, Jorge Sutherland, James D. Zapata-Pavas, L. Estefanía |
| 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 |
| collection | UCrea Repositorio Abierto de la Universidad de Cantabria |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_9362f75168a5caeca4e43c2f1ecedcc2 |
| institution | Universidad de Cantabria (UC) |
| instname_str | Universidad de Cantabria (UC) |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:repositorio.unican.es:10902/34432 |
| publishDate | 2024 |
| publishDateSort | 2024 |
| publisher | Cell Press Elsevier |
| publisherStr | Cell Press Elsevier |
| reponame_str | UCrea Repositorio Abierto de la Universidad de Cantabria |
| spelling | 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 DILI APAP NEDD8 Mitochondria Necrosis 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. 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 Elsevier https://hdl.handle.net/10902/34432 |
| spellingShingle | Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway Gil-Pitarch, Clàudia DILI APAP NEDD8 Mitochondria Necrosis |
| title | 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_short | 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 |
| topic | DILI APAP NEDD8 Mitochondria Necrosis |
| topic_facet | DILI APAP NEDD8 Mitochondria Necrosis |
| url | https://hdl.handle.net/10902/34432 |