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; María Luz Martínez-Chantar

doi:10.1038/s41467-017-01970-x

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

Nat Commun. 2017 Dec 12;8(1):2068. doi: 10.1038/s41467-017-01970-x.

Authors

Lucía Barbier-Torres¹, Paula Iruzubieta^{1

2}, David Fernández-Ramos¹, Teresa C Delgado¹, Daniel Taibo¹, Virginia Guitiérrez-de-Juan¹, Marta Varela-Rey¹, Mikel Azkargorta³, Nicolas Navasa⁴, Pablo Fernández-Tussy¹, Imanol Zubiete-Franco¹, Jorge Simon¹, Fernando Lopitz-Otsoa¹, Sofia Lachiondo-Ortega¹, Javier Crespo², Steven Masson⁵, Misti Vanette McCain⁶, Erica Villa⁷, Helen Reeves^{5

6}, Felix Elortza³, Maria Isabel Lucena⁸, Maria Isabel Hernández-Alvarez^{9

10

11}, Antonio Zorzano^{9

10

11}, Raúl J Andrade⁸, Shelly C Lu¹², José M Mato¹, Juan Anguita^{4

13}, Mercedes Rincón¹⁴, María Luz Martínez-Chantar¹⁵

Affiliations

¹ Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
² 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, 39008, Spain.
³ Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, 48160, Spain.
⁴ Macrophage and Tick Vaccine Laboratory, CIC bioGUNE, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
⁵ The Liver Unit, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE2 7DN, UK.
⁶ Northern Institute of Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 7DN, UK.
⁷ Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, 41124, Italy.
⁸ University Hospital Virgen de la Victoria, Málaga, 29010, Spain.
⁹ Institute for Research in Biomedicine (IRB Barcelona), Barcelona, 08028, Spain.
¹⁰ Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, 08028, Spain.
¹¹ CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain.
¹² Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, 90048, CA, USA.
¹³ Ikerbasque, Basque Foundation for Science, Bilbao, 48013, Spain.
¹⁴ Department of Medicine, University of Vermont College of Medicine, Burlington, 05405, VT, USA. mercedes.rincon@uvm.edu.
¹⁵ Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain. mlmartinez@cicbiogune.es.

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.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetaminophen / toxicity*
Adolescent
Adult
Animals
Chemical and Drug Induced Liver Injury / drug therapy*
Chemical and Drug Induced Liver Injury / etiology
Chemical and Drug Induced Liver Injury / pathology*
Disease Models, Animal
Drug Overdose / complications
Drug Overdose / etiology
Electron Transport Complex I / metabolism
Female
Gene Knockout Techniques
HSP40 Heat-Shock Proteins / antagonists & inhibitors
HSP40 Heat-Shock Proteins / metabolism*
Hepatocytes
Humans
Liver / cytology
Liver / pathology
Male
Mice
Mice, Inbred C57BL
Middle Aged
Mitochondria, Liver / metabolism*
Mitochondrial Proteins / antagonists & inhibitors
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism*
Molecular Chaperones / antagonists & inhibitors
Molecular Chaperones / genetics
Molecular Chaperones / metabolism*
Primary Cell Culture
RNA, Small Interfering / metabolism
Rotenone / pharmacology
Rotenone / therapeutic use
Uncoupling Agents / pharmacology
Uncoupling Agents / therapeutic use
Young Adult

Substances

DNAJC15 protein, human
HSP40 Heat-Shock Proteins
Mcj protein, mouse
Mitochondrial Proteins
Molecular Chaperones
RNA, Small Interfering
Uncoupling Agents
Rotenone
Acetaminophen
Electron Transport Complex I

Abstract

Publication types

MeSH terms

Substances

Grants and funding