Heme oxygenase-1 protects liver against ischemia/reperfusion injury via phosphoglycerate mutase family member 5-mediated mitochondrial quality control
Heme oxygenase-1 protects liver against ischemia/reperfusion injury via phosphoglycerate mutase family member 5-mediated mitochondrial quality control
复制标题
血红素加氧酶-1通过磷酸甘油酸变位酶家族成员5介导的线粒体质量控制，保护肝脏免受缺血/再灌注损伤
DOI：
10.1016/j.lfs.2018.03.017
复制
发表时间：
2018-05-01
期刊：
影响因子：
6.1
通讯作者：
Lee, Sun-Mee
中科院分区：
文献类型：
--
作者：
Hong, Jeong-Min;Lee, Sun-Mee
目的：血红素加氧酶-1 （Heme oxygenase-1, HO-1）是一种内源性的细胞保护酶，在应激条件下可定位于线粒体，对线粒体功能的维持起作用。线粒体质量控制（QC）对细胞健康和与氧化还原稳态相关的恢复至关重要。近年来研究报道，磷酸甘油酸突变酶家族成员（PGAM） 5是线粒体内的一种磷酸酶，在线粒体内稳态中起着关键作用。因此，我们旨在研究HO-1在I/ r诱导的肝损伤中的细胞保护机制，重点关注与PGAM5信号传导相关的线粒体QC。主要方法：小鼠肝缺血60 min后再灌注6 h，缺血前16 h和3 h分别用血红素（HO-1诱导剂，30 mg/kg）或原卟啉锌（ZnPP； HO-1抑制剂，10 mg/kg）预处理2次。主要发现：I/R增加了肝脏和线粒体HO活性，血红蛋白增强了HO活性。血红素可减轻I/ r诱导的肝细胞和线粒体损伤，ZnPP可增强肝细胞和线粒体损伤。同时，I/R增加了线粒体的生物发生，线粒体DNA含量和线粒体转录因子A蛋白表达增加。Hemin增强了这些结果。I/R损伤了有丝分裂，表现为Parkin蛋白表达和有丝分裂空泡数量的减少。这些变化被血红蛋白减弱。Hemin减弱了I/ r诱导的线粒体分裂相关蛋白、动力蛋白相关蛋白1的升高和PGAM5蛋白表达的降低。此外，PGAM5 siRNA消除了HO-1对缺氧/再氧化HepG2细胞线粒体QC的影响。意义：我们的研究结果表明，HO-1通过PGAM5信号通路调控线粒体QC来保护I/ r诱导的肝损伤。
Aims: Heme oxygenase-1 (HO-1), an endogenous cytoprotective enzyme, is reported that can be localized in mitochondria under stress, contributing to preserve mitochondrial function. Mitochondrial quality control (QC) is essential to cellular health and recovery linked with redox homeostasis. Recent studies reported that phosphoglycerate mutase family member (PGAM) 5, a mitochondria-resident phosphatase, plays critical role in mitochondrial homeostasis. Therefore, we aim to investigate cytoprotective mechanisms of HO-1 in I/R-induced hepatic injury focusing on mitochondrial QC associated with PGAM5 signaling.Main methods: Mice were subjected to 60 min of hepatic ischemia followed by 6 h reperfusion and were pre-treated twice with hemin (HO-1 inducer, 30 mg/kg) or zinc protoporphyrin (ZnPP; HO-1 inhibitor, 10 mg/kg) 16 and 3 h before ischemia.Key findings: I/R increased hepatic and mitochondrial HO activity, which was augmented by hemin. I/R-induced hepatocellular and mitochondrial damages were attenuated by hemin and augmented by ZnPP. Meanwhile, I/R increased mitochondrial biogenesis, as evidenced by increased mitochondrial DNA contents and mitochondrial transcription factor A protein expression. Hemin augmented these results. I/R impaired mitophagy, as indicated by decreases in Parkin protein expression and the number of mitophagic vacuoles. These changes were attenuated by hemin. Hemin attenuated the I/R-induced increase in mitochondrial fission-related protein, dynamin-related protein 1, and the decrease in PGAM5 protein expression. Furthermore, PGAM5 siRNA abolished the effect of HO-1 on mitochondrial QC in HepG2 cells subjected to hypoxia/reoxygenation.Significance: Our findings suggest that HO-1 protects against I/R-induced hepatic injury via regulation of mitochondrial QC by PGAM5 signaling.