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

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 Fernández-Tussy, Imanol Zubiete-Franco, Jorge Simon, Fernando Lopitz-Otsoa, Sofia Lachiondo-Ortega, Javier Crespo, Steven Masson, Misti Vanette McCain, Erica Villa, Helen Reeves, Felix Elortza, Maria Isabel Lucena, Maria Isabel Hernández-Alvarez, Antonio Zorzano, Raúl J. Andrade, Shelly C. Lu, José M. Mato, Juan Anguita, Mercedes Rincón () and María Luz Martínez-Chantar ()
Additional contact information
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
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
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)
Antonio Zorzano: Institute for Research in Biomedicine (IRB Barcelona)
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
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

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01970-x

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