2. Academic Validation
  3. Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway

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

  • Cell Rep Med. 2024 Jul 16;5(7):101653. doi: 10.1016/j.xcrm.2024.101653.
Clàudia Gil-Pitarch 1,  Marina Serrano-Maciá 1,  Jorge Simon 1,  Laura Mosca 2,  Carolina Conter 1,  Claudia M Rejano-Gordillo 3,  L Estefanía Zapata-Pavas 1,  Patricia Peña-Sanfélix 1,  Mikel Azkargorta 4,  Rubén Rodríguez-Agudo 1,  Sofía Lachiondo-Ortega 1,  Maria Mercado-Gómez 1,  Teresa C Delgado 1,  Marina Porcelli 2,  Igor Aurrekoetxea 5,  James D Sutherland 6,  Rosa Barrio 6,  Dimitris Xirodimas 7,  Patricia Aspichueta 8,  Felix Elortza 9,  Luis Alfonso Martínez-Cruz 1,  Rubén Nogueiras 10,  Paula Iruzubieta 11,  Javier Crespo 11,  Steven Masson 12,  Misti Vanette McCain 13,  Helen L Reeves 12,  Raul J Andrade 14,  M Isabel Lucena 15,  Ugo Mayor 16,  Naroa Goikoetxea-Usandizaga 17,  Irene González-Recio 18,  María L Martínez-Chantar 19
Affiliations

Affiliations

  • 1 Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain.
  • 2 Department of Life Sciences, Health and Health Professions, Link University, Via del Casale di San Pio V, 44 00165 Rome, Italy.
  • 3 Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain; Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, University Institute of Biosanitary Research of Extremadura (INUBE), 06071 Badajoz, Spain.
  • 4 Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), ProteoRed-ISCIII, CIBERehd, Science and Technology Park of Bizkaia, 48160 Derio, Spain.
  • 5 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain; Biobizkaia Health Research Institute, 48903 Barakaldo, Spain.
  • 6 Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain.
  • 7 CRBM, University Montpellier, CNRS, 34293 Montpellier, France.
  • 8 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain; Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain.
  • 9 Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), ProteoRed-ISCIII, CIBERehd, Science and Technology Park of Bizkaia, 48160 Derio, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain.
  • 10 Department of Physiology, School of Medicine-Instituto de Investigaciones Sanitarias, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain; Department of Physiology, CIMUS, 15782 University of Santiago de Compostela, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain; Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain.
  • 11 Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, 39011 Santander, Spain.
  • 12 The Liver Unit, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, NE7 7DN Newcastle upon Tyne, UK; Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
  • 13 Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
  • 14 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain; Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29590 Málaga, Spain.
  • 15 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, UICEC SCReN, Universidad de Málaga, 29590 Málaga, Spain.
  • 16 Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain.
  • 17 Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain.
  • 18 Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain. Electronic address: irecio@cicbiogune.es.
  • 19 Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain. Electronic address: mlmartinez@cicbiogune.es.
PMID: 39019009 DOI: 10.1016/j.xcrm.2024.101653
Abstract

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.

Keywords

APAP; DILI; NEDD8; mitochondria; necrosis.

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