He Xue, Liang Shi-Min, Wang Hong-Qian, Tao Li, Sun Fei-Fei, Wang Yan, Zhang Cheng, Huang Yi-Chao, Xu De-Xiang, Chen Xi
Department of Gastroenterology, Anhui Provincial Key Laboratory of Digestive Disease, the First Affiliated Hospital of Anhui Medical University, Hefei 230032, China.
Department of Toxicology, Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China.
Toxicol Appl Pharmacol. 2023 Apr 15;465:116452. doi: 10.1016/j.taap.2023.116452. Epub 2023 Mar 7.
Mitochondrial oxidative stress has been a crucial mediator in acetaminophen (APAP)-induced hepatotoxicity. MitoQ, an analog of coenzyme Q10, is targeted towards mitochondria and acts as a potent antioxidant. This study aimed to explore the effect of MitoQ on APAP-induced liver injury and its possible mechanisms. To investigate this, CD-1 mice and AML-12 cells were treated with APAP. Hepatic MDA and 4-HNE, two markers of lipid peroxidation (LPO), were elevated as early as 2 h after APAP. Oxidized lipids were rapidly upregulated in APAP-exposed AML-12 cells. Hepatocyte death and mitochondrial ultrastructure alterations were observed in APAP-induced acute liver injury. The in vitro experiments showed that mitochondrial membrane potentials and OXPHOS subunits were downregulated in APAP-exposed hepatocytes. MtROS and oxidized lipids were elevated in APAP-exposed hepatocytes. We discovered that APAP-induced hepatocyte death and liver injury were ameliorated by attenuation of protein nitration and LPO in MitoQ-pretreated mice. Mechanistically, knockdown of GPX4, a key enzyme for LPO defense systems, exacerbated APAP-induced oxidized lipids, but did not influence the protective effect of MitoQ on APAP-induced LPO and hepatocyte death. Whereas knockdown of FSP1, another key enzyme for LPO defense systems, had little effect on APAP-induced lipid oxidation but partially weakened the protection of MitoQ on APAP-induced LPO and hepatocyte death. These results suggest that MitoQ may alleviate APAP-evoked hepatotoxicity by eliminating protein nitration and suppressing hepatic LPO. MitoQ prevents APAP-induced liver injury partially dependent of FSP1 and independent of GPX4.
线粒体氧化应激一直是对乙酰氨基酚（APAP）诱导的肝毒性的关键介质。MitoQ是辅酶Q10的类似物，靶向线粒体并作为一种有效的抗氧化剂。本研究旨在探讨MitoQ对APAP诱导的肝损伤的影响及其可能机制。为此，用APAP处理CD-1小鼠和AML-12细胞。早在APAP处理后2小时，脂质过氧化（LPO）的两个标志物肝丙二醛（MDA）和4-羟基壬烯醛（4-HNE）就升高了。在暴露于APAP的AML-12细胞中，氧化脂质迅速上调。在APAP诱导的急性肝损伤中观察到肝细胞死亡和线粒体超微结构改变。体外实验表明，暴露于APAP的肝细胞中线粒体膜电位和氧化磷酸化（OXPHOS）亚基下调。暴露于APAP的肝细胞中，线粒体活性氧（MtROS）和氧化脂质升高。我们发现，在MitoQ预处理的小鼠中，通过减轻蛋白质硝化和LPO，APAP诱导的肝细胞死亡和肝损伤得到改善。机制上，LPO防御系统的关键酶谷胱甘肽过氧化物酶4（GPX4）的敲低加剧了APAP诱导的氧化脂质，但不影响MitoQ对APAP诱导的LPO和肝细胞死亡的保护作用。而LPO防御系统的另一个关键酶铁死亡抑制蛋白1（FSP1）的敲低对APAP诱导的脂质氧化影响不大，但部分削弱了MitoQ对APAP诱导的LPO和肝细胞死亡的保护作用。这些结果表明，MitoQ可能通过消除蛋白质硝化和抑制肝脏LPO来减轻APAP诱发的肝毒性。MitoQ预防APAP诱导的肝损伤部分依赖于FSP1且独立于GPX4。
