Hepatitis B Virus X protein elevates Parkin-mediated mitophagy through Lon Peptidase in starvation

• Published in: Experimental cell research 2018-07, Vol.368 (1), p.75-83
• Main Authors: Huang, Xiao-Yun, Li, Dan, Chen, Zhi-Xin, Huang, Yue-Hong, Gao, Wen-Yu, Zheng, Bi-Yun, Wang, Xiao-Zhong
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; APOPTOSIS; Carcinoma, Hepatocellular - metabolism; Cell Line; HEPATITIS; Hepatitis B - virology; Hepatitis B Virus X protein; Hepatocellular Carcinoma; HEPATOMAS; Humans; Liver Neoplasms - virology; Lon Peptidase; MITOCHONDRIA; Mitochondria - virology; Mitochondrial Degradation - physiology; Mitophagy; NUTRIENTS; Parkin; Peptide Hydrolases - metabolism; Protein Kinases - metabolism; Trans-Activators - metabolism; VIRUSES
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2018.04.016

Hepatocellular Carcinoma (HCC) is the fifth most prevalent cancer worldwide. Specially, Hepatitis B viurs X protein (HBx) is a leading factor in the progression of Hepatitis B viurs-related HCC. Nutrient-deprived tumor microenvironment also contributes to tumor development. However, the role of HBx in nutrient-deprived HCC has received little investigation. Here, we show that HBx elevates PINK1-Parkin mediating mitophagy in starvation. HBx not only increases the PINK1/Parkin gene expression but also accelerates Parkin recruitment to partial mitochondria. Further analysis indicates that, HBx either promotes mitochondrial unfolded protein response, with remarkable mitochondrial LONP1 increases, or reduces LONP1 expression in cytosol inducing LONP1-Parkin pathway, both consequently enhancing mitophagy. Moreover, the enhanced mitophagy lowers mitochondrial apoptosis in starved hepatoma cells, and Bax is implied in the machinery. In addition, we define differential centrifuge, 3000 g or 12,000 g to pellet mitochondria, as an effective method to obtain distinct mitochondria. In collect, HBx regulates diverse aspects of LONP1 and Parkin, enhancing mitophagy in starvation. This study may shed new insights into the machinery development of hepatocellular carcinoma. •HBx induces the translocation of Parkin to partial mitochondria to elevate mitophagy.•HBx has diverse roles on mitochondrial and cytosolic LONP1 to enhance mitophagy.•HBx attenuates mitochondrial apoptosis in starvation through enhancing mitophagy.