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

• Published in: Nature communications Vol. 8; no. 1; pp. 2068 - 11
• Main Authors: Barbier-Torres, Lucía, Iruzubieta, Paula, Fernández-Ramos, David, Delgado, Teresa C., Taibo, Daniel, Guitiérrez-de-Juan, Virginia, Varela-Rey, Marta, Azkargorta, Mikel, Navasa, Nicolas, Fernández-Tussy, Pablo, Zubiete-Franco, Imanol, Simon, Jorge, Lopitz-Otsoa, Fernando, Lachiondo-Ortega, Sofia, Crespo, Javier, Masson, Steven, McCain, Misti Vanette, Villa, Erica, Reeves, Helen, Elortza, Felix, Lucena, Maria Isabel, Hernández-Alvarez, Maria Isabel, Zorzano, Antonio, Andrade, Raúl J., Lu, Shelly C., Mato, José M., Anguita, Juan, Rincón, Mercedes, Martínez-Chantar, María Luz
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.12.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/80/642/333; 692/4020/4021/1607/2749; Acetaminophen; Acetaminophen - toxicity; Acetylcysteine; Adolescent; Adult; Analgesics; Animals; Biocompatibility; 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; Down-regulation; Drug Overdose - complications; Drug Overdose - etiology; Electron Transport Complex I - metabolism; Female; Fever; Gene Knockout Techniques; Hepatocytes; HSP40 Heat-Shock Proteins - antagonists & inhibitors; HSP40 Heat-Shock Proteins - metabolism; Humanities and Social Sciences; Humans; Injury prevention; Liver; Liver - cytology; Liver - pathology; Liver diseases; Male; Mice; Mice, Inbred C57BL; Middle Aged; Mitochondria; Mitochondria, Liver - metabolism; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular Chaperones - antagonists & inhibitors; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; multidisciplinary; Overdose; Pain; Primary Cell Culture; RNA, Small Interfering - metabolism; Rotenone - pharmacology; Rotenone - therapeutic use; Science; Science (multidisciplinary); Toxicity; Uncoupling Agents - pharmacology; Uncoupling Agents - therapeutic use; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01970-x

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. Acetaminophen-induced liver injury is one of the most common causes of liver failure and has to be treated within hours of the overdose. Here Barbier-Torres et al. show that targeting MCJ, a mitochondrial negative regulator, even 24 h after the overdose protects liver from acetaminophen-induced damage.