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.

Details

Title
The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury
Author
Barbier-Torres, Lucía 1 ; Iruzubieta, Paula 2 ; Fernández-Ramos, David 1 ; Delgado, Teresa C 1 ; Taibo, Daniel 1 ; Guitiérrez-de-Juan, Virginia 1 ; Varela-Rey, Marta 1 ; Azkargorta, Mikel 3 ; Navasa, Nicolas 4 ; Fernández-Tussy, Pablo 1 ; Zubiete-Franco, Imanol 1 ; Simon, Jorge 1 ; Fernando Lopitz-Otsoa 1 ; Lachiondo-Ortega, Sofia 1 ; Crespo, Javier 5 ; Masson, Steven 6 ; McCain, Misti Vanette 7 ; Villa, Erica 8   VIAFID ORCID Logo  ; Reeves, Helen 9 ; Elortza, Felix 3 ; Lucena, Maria Isabel 10   VIAFID ORCID Logo  ; Hernández-Alvarez, Maria Isabel 11   VIAFID ORCID Logo  ; Zorzano, Antonio 11 ; Andrade, Raúl J 10 ; Lu, Shelly C 12 ; Mato, José M 1 ; Anguita, Juan 13   VIAFID ORCID Logo  ; Rincón, Mercedes 14 ; María Luz Martínez-Chantar 1 

1  Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, Bizkaia, Spain 
2  Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, Bizkaia, Spain; Department of Gastroenterology and Hepatology, 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), Santander, Spain 
3  Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, Spain 
4  Macrophage and Tick Vaccine Laboratory, CIC bioGUNE, Bizkaia Science and Technology Park, Derio, Bizkaia, Spain 
5  Department of Gastroenterology and Hepatology, 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), Santander, Spain 
6  The Liver Unit, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 
7  Northern Institute of Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, UK 
8  Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy 
9  The Liver Unit, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Northern Institute of Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, UK 
10  University Hospital Virgen de la Victoria, Málaga, Spain 
11  Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain 
12  Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USA 
13  Macrophage and Tick Vaccine Laboratory, CIC bioGUNE, Bizkaia Science and Technology Park, Derio, Bizkaia, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain 
14  Department of Medicine, University of Vermont College of Medicine, Burlington, VT, USA 
Pages
1-11
Publication year
2017
Publication date
Dec 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-01970-x
ProQuest document ID
1983424232
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.