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
  • 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: [email protected].
  • 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: [email protected].
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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