Article Dans Une Revue Cell Reports Medicine Année : 2024

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

1 CIC bioGUNE - Center for Cooperative Research in Biosciences = Centro de Investigación cooperativa en biociencia (Derio, Biscay, Espagne)
2 BRTA - Basque Research and Technology Alliance
3 Link Campus University [Roma] = Università degli Studi Link [Roma]
4 UEX - Universidad de Extremadura - University of Extremadura
5 CIBERehd - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas = Biomedical Research Network Center for Liver and Digestive Diseases [Madrid]
6 UPV / EHU - Universidad del País Vasco [Espainia] / Euskal Herriko Unibertsitatea [España] = University of the Basque Country [Spain] = Université du pays basque [Espagne]
7 CRBM - Centre de recherche en Biologie cellulaire de Montpellier
8 IDIS - Instituto de Investigación Sanitaria de Santiago de Compostela / Health Research Institute of Santiago de Compostela
9 USC - Universidade de Santiago de Compostela [España] = University of Santiago de Compostela [Spain] = Université de Saint-Jacques-de-Compostelle [Espagne]
10 Hospital Universitario Marqués de Valdecilla = Marqués de Valdecilla University Hospital [Santander]
11 IDIVAL - Marqués de Valdecilla Research Institute - Instituto de Investigación Marqués de Valdecilla [Santander]
12 Newcastle University [Newcastle]
13 Newcastle Upon Tyne Hospitals NHS Foundation Trust
14 Universidad de Málaga [Málaga] = University of Málaga [Málaga]
15 IBIMA Plataforma BIONAND - Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform
16 Hospital Universitario Virgen de la Victoria = Virgen de la Victoria University Hospital
17 Ikerbasque - Basque Foundation for Science
Luis Alfonso Martínez-Cruz
  • Fonction : Auteur
Misti Vanette Mccain
  • Fonction : Auteur

Résumé

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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hal-05337527 , version 1 (29-10-2025)

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Clàudia Gil-Pitarch, Marina Serrano-Maciá, Jorge Simon, Laura Mosca, Carolina Conter, et al.. Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway. Cell Reports Medicine, 2024, 5 (7), pp.101653. ⟨10.1016/j.xcrm.2024.101653⟩. ⟨hal-05337527⟩
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