The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury.
The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury.
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DOI：
10.1038/s41467-017-01970-x
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发表时间：
2017-12-12
影响因子：
16.6
通讯作者：
Martínez-Chantar ML
中科院分区：
文献类型：
--
作者：
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;Rincón M;Martínez-Chantar ML
对乙酰氨基酚(APAP)是世界上许多用于治疗疼痛和发烧的药物的活性成分。它的过度使用会引起肝脏损伤，是导致肝功能衰竭的第二大常见原因。线粒体功能障碍导致APAP肝损伤，但APAP引起肝细胞毒性的机制尚不完全清楚。因此，我们缺乏有效的治疗策略来治疗这种病理。在这里，我们发现APAP通过线粒体负调节因子MCJ干扰线粒体呼吸超复合体的形成，并导致ATP产生减少和ROS产生增加。在标准疗法N-乙酰半胱氨酸无效的情况下，使用MCJ表达抑制剂在体内治疗可以保护肝脏免受对乙酰氨基酚引起的肝损伤。我们还发现扑热息痛过量患者的肝脏中MCJ水平升高。提示消炎痛可能是预防和抢救对乙酰氨基酚所致肝损伤的治疗靶点。对乙酰氨基酚引起的肝损伤是导致肝功能衰竭的最常见原因之一，必须在服药过量后几个小时内进行治疗。这里，Barbier-Torres等人。结果表明，靶向mcj，线粒体负调控因子，即使在过量服药24 h后，也能保护肝脏免受对乙酰氨基酚引起的损伤。
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.
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影响因子：
4.8
作者：
Tammineni, Prasad;Anugula, Chandrashekhar;Sepuri, Naresh Babu Venkata
通讯作者：
Sepuri, Naresh Babu Venkata
影响因子：
29
作者：
Chen YC;Taylor EB;Dephoure N;Heo JM;Tonhato A;Papandreou I;Nath N;Denko NC;Gygi SP;Rutter J
通讯作者：
Rutter J
DOI：
10.1038/mtna.2015.23
发表时间：
2015-09-15
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Lam JK;Chow MY;Zhang Y;Leung SW
通讯作者：
Leung SW
影响因子：
2.5
作者：
Mayoral, W;Lewis, JH;Zimmerman, H
通讯作者：
Zimmerman, H
影响因子：
158.5
作者：
SMILKSTEIN, MJ;KNAPP, GL;RUMACK, BH
通讯作者：
RUMACK, BH