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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Detalles Bibliográficos
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
Descripción
Sumario: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.

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