Published July 16, 2024 | Version v1
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Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway

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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 un- der 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.

Notes

This work was supported by grants from Ministerio de Ciencia, Innovacio ́ n y Universidades MICINN: PID2020-117116RB-I00 CEX2021-001136-S inte- grado en el Plan Estatal de Investigacio ́ n Cient ́ıfica y Te ́ cnica e Innovacio ́ n, co- financiado con Fondos FEDER (for M.L.M.-C.); Ministerio de Ciencia e Innova- cio ́n, Programa Retos-Colaboracio ́n RTC2019-007125-1 (for M.L.M.-C.); Instituto de Salud Carlos III, Proyectos Investigacio ́ n 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 Fundacio ́ n Cientı ́fica AECC para proyectos coordinados (IGTP-AECC_2022-042) (for M.L.M.-C.); Transferencia tecnolo ́ gica 2022 (6/12/TT/2022/00001) (for M.L.M.-C.); Desar- rollo Tecnolo ́ gico en Salud (DTS20/00138) (for M.L.M.-C.); Ayudas a proyectos de investigacio ́ n 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, Innovacio ́ n y Universidades-Agencia Estatal de Investigacio ́ n 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 con- tract Margarita Salas (University of Extremadura) from the Program of Requa- lification 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 Minis- terio de Ciencia e Innovacio ́n (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 Begon ̃ a Rodrı ́guez Iruretagoyena for her technical support.

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1Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
2Department of Life Sciences, Health and Health Professions, Link University, Via del Casale di San Pio V, 44 00165 Rome, Italy 3Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, University Institute of Biosanitary Research of Extremadura (INUBE), 06071 Badajoz, Spain
4Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), ProteoRed-ISCIII, CIBERehd, Science and Technology Park of Bizkaia, 48160 Derio, Spain
5Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain 6Biobizkaia Health Research Institute, 48903 Barakaldo, Spain
7Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
8CRBM, University Montpellier, CNRS, 34293 Montpellier, France
9Department of Physiology, School of Medicine-Instituto de Investigaciones Sanitarias, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain
10Department of Physiology, CIMUS, 15782 University of Santiago de Compostela, Santiago de Compostela, Spain
11CIBER Fisiopatologia de la Obesidad y Nutricio ́ n (CIBERobn), Santiago de Compostela, Spain
12Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain
13Gastroenterology and Hepatology Department, Marque ́ s de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, 39011 Santander, Spain
14The Liver Unit, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, NE7 7DN Newcastle upon Tyne, UK

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2024 Gil-Pitarch 2024 Cell Reports Medicine copy.pdf

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DOI
10.1016/j.xcrm.2024.101653

Dates

Accepted
2024-07-16