TFAM公司
MFN2型
褪黑素
品脱1
粒体自噬
线粒体生物发生
线粒体分裂
DNM1L型
线粒体
内分泌学
生物
内科学
第一季
线粒体融合
细胞生物学
自噬
细胞凋亡
线粒体DNA
医学
生物化学
基因
作者
Jung‐Woo Kang,Jin Woo Hong,Sun-Mee Lee
摘要
Abstract 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 ( CC l 4 ) 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 CC l 4 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 β 1 and α ‐smooth muscle actin in response to CC l 4 were attenuated by melatonin. Melatonin attenuated hallmarks of mitochondrial dysfunction, such as mitochondrial swelling and glutamate dehydrogenase release. Chronic CC l 4 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 ( PINK 1); Parkin; peroxisome proliferator‐activated receptor‐gamma coactivator 1 α ( PGC ‐1 α ); nuclear respiratory factor 1 ( NRF 1); and transcription factor A, mitochondrial ( TFAM ). CC l 4 ‐mediated decreases in mitochondrial fission‐ and fusion‐related proteins, such as dynamin‐related protein 1 ( DRP 1) 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.
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