Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
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.
Nat Commun. 2017 Dec 12;8(1):2068. 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.
对乙酰氨基酚（APAP）是世界范围内许多用于治疗疼痛和发热的药物中的有效成分。其过量使用会导致肝损伤，是肝衰竭的第二大常见原因。线粒体功能障碍导致 APAP 诱导的肝损伤，但 APAP 导致肝细胞毒性的确切机制尚不完全清楚。因此，我们缺乏有效治疗这种疾病的策略。在这里，我们表明 APAP 通过线粒体负调节剂 MCJ 干扰线粒体呼吸超级复合物的形成，并导致 ATP 生成减少和 ROS 生成增加。当标准治疗药物 N-乙酰半胱氨酸无效时，体内用 MCJ 表达抑制剂治疗可保护肝脏免受 APAP 诱导的肝损伤。我们还发现，在过量服用 APAP 的患者的肝脏中，MCJ 的水平升高。我们认为，MCJ 可能代表一种治疗靶点，以预防和挽救由 APAP 引起的肝损伤。
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