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  2. Activation of mitophagy by rapamycin eliminated the accumulation of TDP-43 on mitochondrial and promoted the resolution of carbon tetrachloride-induced liver fibrosis in mice

Activation of mitophagy by rapamycin eliminated the accumulation of TDP-43 on mitochondrial and promoted the resolution of carbon tetrachloride-induced liver fibrosis in mice

  • Toxicology. 2022 Apr 9;471:153176. doi: 10.1016/j.tox.2022.153176.
Hui Yong 1 Shulin Shan 1 Shuai Wang 1 Zhidan Liu 1 Zhaoxiong Liu 1 Cuiqin Zhang 1 Yiyu Yang 1 Zhengcheng Huang 1 Fuyong Song 2
Affiliations

Affiliations

  • 1 Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 2 Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: fysong3707@sdu.edu.cn.
Abstract

Liver fibrosis can lead to liver cirrhosis and hepatocellular carcinoma, and no effective treatment is available in clinical practice. Mitochondrial dysfunction is thought to be closely related to the development of liver fibrosis. Recent studies have reported that abnormal accumulation of TDP-43 on mitochondria may interfere with mitochondrial function in neurodegenerative disorders. However, whether aberrant TDP-43 aggregation is also involved in liver fibrosis has not been investigated. In this study, C57/BL6 mice were treated with CCl4 (escalating doses, three times a week) for 8 weeks to establish a model of liver fibrosis. Furthermore, Mitophagy intervention experiment was achieved by the activator rapamycin (RAPA). The results demonstrated that chronic CCl4 exposure resulted in severe mitochondrial damage, inflammatory response and hepatic fibrogenesis. Interestingly, abnormal aggregation of TDP-43 on mitochondria was observed. By contrast, RAPA administration could promote the regression of liver fibrosis. Mechanistically, RAPA could eliminate the accumulation of TDP-43 on mitochondrial through enhancing Mitophagy, thereby improving mitochondrial function. Taken together, our study revealed that mitochondrial damage induced by abnormal accumulation of TDP-43 has been implicated in the progression of liver fibrosis. Targeted clearance of mitochondrial TDP-43 may lead to the development of some anti-fibrotic therapies.

Keywords

Carbon tetrachloride; Liver fibrosis; Mitophagy; TDP-43.

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