Iruzubieta Paula, 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, Milkiewicz Malgorzata, Milkiewicz Piotr, Anguita Juan, Monte María J, Marin José J G, López-Hoyos Marcos, Delgado Teresa C, Rincón Mercedes, Crespo Javier, Martínez-Chantar María Luz
Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain.
Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.
JHEP Rep. 2021 Mar 18;3(3):100276. doi: 10.1016/j.jhepr.2021.100276. eCollection 2021 Jun.
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.
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.
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 model of bile-acid induced toxicity, we observed that the loss of MCJ protected mouse primary hepatocytes from bile acid-induced mitochondrial ROS overproduction and ATP depletion, enabling higher cell viability. Finally, the inhibition of the MCJ expression, following BDL, showed reduced liver injury and a mitigation of the main cholestatic characteristics.
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.
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.
线粒体是细胞内活性氧（ROS）形成的主要细胞器，线粒体功能障碍被认为是胆汁淤积性肝病发病机制中的关键因素。甲基化控制的J蛋白（MCJ）是一种线粒体蛋白，它与电子传递链复合体I相互作用并抑制其功能。MCJ在胆汁淤积病理学中的相关性尚未得到探索。
我们研究了慢性胆汁淤积性肝病患者肝活检组织以及野生型和MCJ基因敲除（MCJ-KO）小鼠的肝脏和原代肝细胞中MCJ与胆汁淤积诱导的肝损伤之间的关系。胆管结扎（BDL）被用作胆汁淤积的动物模型，原代肝细胞用毒性剂量的胆汁酸处理。我们评估了MCJ沉默对胆汁淤积诱导的肝损伤的治疗效果。
与正常肝组织相比，慢性胆汁淤积性肝病患者肝组织中MCJ水平升高。同样，在小鼠模型中，肝脏中MCJ水平也升高。BDL后，MCJ-KO动物的炎症和细胞凋亡明显减少。在胆汁酸诱导的毒性模型中，我们观察到MCJ缺失可保护小鼠原代肝细胞免受胆汁酸诱导的线粒体ROS过度产生和ATP耗竭，从而使细胞活力更高。最后，BDL后抑制MCJ表达可减轻肝损伤并缓解主要胆汁淤积特征。
我们证明MCJ参与胆汁淤积性肝损伤的进展，我们的结果确定MCJ是减轻胆汁淤积引起的肝损伤的潜在治疗靶点。
在本研究中，我们研究了MCJ对线粒体呼吸链的抑制作用对胆汁酸诱导的肝毒性的影响。MCJ缺失可保护肝细胞免受胆汁酸毒性导致的细胞凋亡、线粒体ROS过度产生和ATP耗竭。我们的结果确定MCJ是减轻胆汁淤积性肝病肝损伤的潜在治疗靶点。
