Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis
Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis
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DOI：
10.1111/jpi.12319
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发表时间：
2016-05-01
影响因子：
10.3
通讯作者：
Lee, Sun-Mee
中科院分区：
文献类型：
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作者：
Kang, Jung-Woo;Hong, Jeong-Min;Lee, Sun-Mee
肝纤维化会导致肝硬变和衰竭，目前还没有有效的治疗方法。越来越多的证据支持线粒体功能障碍和肝纤维化之间的联系，基于线粒体质量控制的治疗已成为新的治疗靶点。我们从线粒体吞噬和线粒体生物发生两个方面探讨了褪黑素对线粒体功能障碍所致肝纤维化的保护机制。四氯化碳(CCl4)溶于橄榄油(0.5mL/kg，每周2次，ip)。8周。褪黑素剂量分别为2.5、5和10 mg/kg，每日1次。慢性接触CCl4可诱导胶原沉积、肝细胞损伤和氧化应激，褪黑素可减轻这些增加。褪黑素可减弱CCl4引起的转化生长因子1和-平滑肌肌动蛋白的mRNA和蛋白表达水平的增加。褪黑素可减轻线粒体功能障碍的症状，如线粒体肿胀和谷氨酸脱氢酶释放。慢性接触CCl4会损害有丝分裂和线粒体的生物合成，褪黑素可减轻这种损害，表现为线粒体DNA和PTEN诱导的假定激酶1(PINK1)、Parkin、过氧化物酶体增殖物激活受体-γ共激活因子1(PGC-1)、核呼吸因子1(NRF1)和转录因子A、线粒体(TFAM)的蛋白水平增加。褪黑素也可减弱CCL4介导的线粒体分裂和融合相关蛋白的减少，如动力蛋白相关蛋白1(Drp1)和丝裂原蛋白2。此外，褪黑素还可诱导AMP活化蛋白激酶(AMPK)的磷酸化。这些结果表明，褪黑素通过上调线粒体吞噬和线粒体生物生成来预防肝纤维化，可能是一种有效的抗纤维化治疗方法。
Liver fibrosis leads to liver cirrhosis and failure, and no effective treatment is currently available. Growing evidence supports a link between mitochondrial dysfunction and liver fibrogenesis and mitochondrial quality control-based therapy has emerged as a new therapeutic target. We investigated the protective mechanisms of melatonin against mitochondrial dysfunction-involved liver fibrosis, focusing on mitophagy and mitochondrial biogenesis. Rats were treated with carbon tetrachloride (CCl4) dissolved in olive oil (0.5 mL/kg, twice a week, i.p.) for 8 wk. Melatonin was administered orally at 2.5, 5, and 10 mg/kg once a day. Chronic CCl4 exposure induced collagen deposition, hepatocellular damage, and oxidative stress, and melatonin attenuated these increases. Increases in mRNA and protein expression levels of transforming growth factor 1 and -smooth muscle actin in response to CCl4 were attenuated by melatonin. Melatonin attenuated hallmarks of mitochondrial dysfunction, such as mitochondrial swelling and glutamate dehydrogenase release. Chronic CCl4 exposure impaired mitophagy and mitochondrial biogenesis, and melatonin attenuated this impairment, as indicated by increases in mitochondrial DNA and in protein levels of PTEN-induced putative kinase 1 (PINK1); Parkin; peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC-1); nuclear respiratory factor 1 (NRF1); and transcription factor A, mitochondrial (TFAM). CCl4-mediated decreases in mitochondrial fission- and fusion-related proteins, such as dynamin-related protein 1 (DRP1) and mitofusin 2, were also attenuated by melatonin. Moreover, melatonin induced AMP-activated protein kinase (AMPK) phosphorylation. These results suggest that melatonin protects against liver fibrosis via upregulation of mitophagy and mitochondrial biogenesis, and may be useful as an anti-fibrotic treatment.