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The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury

Author

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  • Lucía Barbier-Torres

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Paula Iruzubieta

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park
    Marqués de Valdecilla University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL))

  • David Fernández-Ramos

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Teresa C. Delgado

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Daniel Taibo

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Virginia Guitiérrez-de-Juan

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Marta Varela-Rey

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Mikel Azkargorta

    (CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park)

  • Nicolas Navasa

    (CIC bioGUNE, Bizkaia Science and Technology Park)

  • Pablo Fernández-Tussy

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Imanol Zubiete-Franco

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Jorge Simon

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Fernando Lopitz-Otsoa

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Sofia Lachiondo-Ortega

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Javier Crespo

    (Marqués de Valdecilla University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL))

  • Steven Masson

    (Newcastle-upon-Tyne Hospitals NHS Foundation Trust)

  • Misti Vanette McCain

    (The Medical School, Newcastle University)

  • Erica Villa

    (Department of Internal Medicine, University of Modena and Reggio Emilia)

  • Helen Reeves

    (Newcastle-upon-Tyne Hospitals NHS Foundation Trust
    The Medical School, Newcastle University)

  • Felix Elortza

    (CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park)

  • Maria Isabel Lucena

    (University Hospital Virgen de la Victoria)

  • Maria Isabel Hernández-Alvarez

    (Institute for Research in Biomedicine (IRB Barcelona)
    Facultat de Biologia, Universitat de Barcelona
    CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III)

  • Antonio Zorzano

    (Institute for Research in Biomedicine (IRB Barcelona)
    Facultat de Biologia, Universitat de Barcelona
    CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III)

  • Raúl J. Andrade

    (University Hospital Virgen de la Victoria)

  • Shelly C. Lu

    (Cedars-Sinai Medical Center)

  • José M. Mato

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

  • Juan Anguita

    (CIC bioGUNE, Bizkaia Science and Technology Park
    Basque Foundation for Science)

  • Mercedes Rincón

    (University of Vermont College of Medicine)

  • María Luz Martínez-Chantar

    (Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park)

Abstract

Acetaminophen (APAP) is the active component of many medications used to treat pain and fever worldwide. Its overuse provokes liver injury and it is the second most common cause of liver failure. Mitochondrial dysfunction contributes to APAP-induced liver injury but the mechanism by which APAP causes hepatocyte toxicity is not completely understood. Therefore, we lack efficient therapeutic strategies to treat this pathology. Here we show that APAP interferes with the formation of mitochondrial respiratory supercomplexes via the mitochondrial negative regulator MCJ, and leads to decreased production of ATP and increased generation of ROS. In vivo treatment with an inhibitor of MCJ expression protects liver from acetaminophen-induced liver injury at a time when N-acetylcysteine, the standard therapy, has no efficacy. We also show elevated levels of MCJ in the liver of patients with acetaminophen overdose. We suggest that MCJ may represent a therapeutic target to prevent and rescue liver injury caused by acetaminophen.

Suggested Citation

  • Lucía Barbier-Torres & Paula Iruzubieta & David Fernández-Ramos & Teresa C. Delgado & Daniel Taibo & Virginia Guitiérrez-de-Juan & Marta Varela-Rey & Mikel Azkargorta & Nicolas Navasa & Pablo Fernánde, 2017. "The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01970-x
    DOI: 10.1038/s41467-017-01970-x
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