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Boosting mitochondria activity by silencing MCJ overcomes cholestasis-induced liver injury

Abstract: Background & Aims: Mitochondria are the major organelles for the formation of reactive oxygen species (ROS) in the cell, and mitochondrial dysfunction has been described as a key factor in the pathogenesis of cholestatic liver disease. The methylation-controlled J-protein (MCJ) is a mitochondrial protein that interacts with and represses the function of complex I of the electron transport chain. The relevance of MCJ in the pathology of cholestasis has not yet been explored. Methods: We studied the relationship between MCJ and cholestasis-induced liver injury in liver biopsies from patients with chronic cholestatic liver diseases, and in livers and primary hepatocytes obtained from WT and MCJ-KO mice. Bile duct ligation (BDL) was used as an animal model of cholestasis, and primary hepatocytes were treated with toxic doses of bile acids. We evaluated the effect of MCJ silencing for the treatment of cholestasis-induced liver injury. Results: Elevated levels of MCJ were detected in the liver tissue of patients with chronic cholestatic liver disease when compared with normal liver tissue. Likewise, in mouse models, the hepatic levels of MCJ were increased. After BDL, MCJ-KO animals showed significantly decreased inflammation and apoptosis. In an in vitro model of bile-acid induced toxicity, we observed that the loss of MCJ protected mouse primary hepatocytes from bile acid-induced mitochondrial ROS over-production and ATP depletion, enabling higher cell viability. Finally, the in vivo inhibition of the MCJ expression, following BDL, showed reduced liver injury and a mitigation of the main cholestatic characteristics. Conclusions: We demonstrated that MCJ is involved in the progression of cholestatic liver injury, and our results identified MCJ as a potential therapeutic target to mitigate the liver injury caused by cholestasis. Lay summary: In this study, we examine the effect of mitochondrial respiratory chain inhibition by MCJ on bile acid-induced liver toxicity. The loss of MCJ protects hepatocytes against apoptosis, mitochondrial ROS overproduction, and ATP depletion as a result of bile acid toxicity. Our results identify MCJ as a potential therapeutic target to mitigate liver injury in cholestatic liver diseases.

 Fuente: JHEP Reports Volume 3, Issue 3, June 2021, 100276

Editorial: Elsevier

 Fecha de publicación: 01/06/2021

Nº de páginas: 13

Tipo de publicación: Artículo de Revista

 DOI: doi.org/10.1016/j.jhepr.2021.100276

ISSN: 2589-5559

Proyecto español: SAF2017-87301-R

Url de la publicación: https://doi.org/10.1016/j.jhepr.2021.100276

Autores/as

PAULA IRUZUBIETA COZ

GOIKOETXEA-USANDIZAGA, NAROA

BARBIER-TORRES, LUCÍA

SERRANO-MACIÁ, MARINA

FERNÁNDEZ-RAMOS,DAVID

FERNÁNDEZ-TUSSY, PABLO

GUTIÉRREZ-DE-JUAN, VIRGINIA

LACHIONDO-ORTEGA, SOFIA

SIMON, JORGE

BRAVO, MIREN

LOPITZ-OTSOA, FERNANDO

ROBLES, MERCEDES

FERRE-ARACIL, CARLOS

VARELA-REY, MARTA

ELGUEZABAL, NATALIA

CALLEJA, JOSÉ LUIS

LU, SHELLY C.