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

Lookup NU author(s): Dr Paula Iruzubieta, Dr Steven Masson, Misti McCain, Professor Helen Reeves

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 metadata

Author(s): Barbier-Torres L, Iruzubieta P, Fernández-Ramos D, Delgado TC, Taibo D, Guitiérrez-de-Juan V, Varela-Rey M, Azkargorta M, Navasa N, Fernández-Tussy P, Zubiete-Franco I, Simon J, Lopitz-Otsoa F, Lachiondo-Ortega S, Crespo J, Masson S, McCain MV, Villa E, Reeves H, Elortza F, Lucena MI, Hernández-Alvarez MI, Zorzano A, Andrade RJ, Lu SC, Mato JM, Anguita J, Rincon M, Martínez-Chantar ML

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2017

Volume: 8

Online publication date: 12/12/2017

Acceptance date: 30/10/2017

Date deposited: 12/12/2017

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-017-01970-x

DOI: 10.1038/s41467-017-01970-x


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