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

Lookup NU author(s): Dr Steven MassonORCiD, Professor Helen ReevesORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).

Abstract

© 2024 The AuthorsDrug-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.

Publication metadata

Author(s): Gil-Pitarch C, Serrano-Macia M, Simon J, Mosca L, Conter C, Rejano-Gordillo CM, Zapata-Pavas LE, Pena-Sanfelix P, Azkargorta M, Rodriguez-Agudo R, Lachiondo-Ortega S, Mercado-Gomez M, Delgado TC, Porcelli M, Aurrekoetxea I, Sutherland JD, Barrio R, Xirodimas D, Aspichueta P, Elortza F, Martinez-Cruz LA, Nogueiras R, Iruzubieta P, Crespo J, Masson S, McCain MV, Reeves HL, Andrade RJ, Lucena MI, Mayor U, Goikoetxea-Usandizaga N, Gonzalez-Recio I, Martinez-Chantar ML

Publication type: Article

Publication status: Published

Journal: Cell Reports Medicine

Year: 2024

Volume: 5

Issue: 7

Online publication date: 16/07/2024

Acceptance date: 19/06/2024

Date deposited: 25/07/2024

ISSN (electronic): 2666-3791

Publisher: Cell Press

URL: https://doi.org/10.1016/j.xcrm.2024.101653

DOI: 10.1016/j.xcrm.2024.101653

Data Access Statement: This paper does not report original code. The mass spectrometry data have been deposited to the ProteomeXchange Consortium (https://proteomecentral. proteomexchange.org) via the iPRoX partner repository: PXD053221. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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