HCV NS5A Disrupts Mitochondrial Dynamics and Induces Mitophagy

HCV NS5A Disrupts Mitochondrial Dynamics and Induces Mitophagy

Alagie Jassey(Alagie Jassey)

指導教授 ： 林良宗

臺北醫學大學/醫學院/醫學科學研究所/碩士(2016年)

摘要

無資料

關鍵字

C型肝炎病毒 ； 粒線體的動態平衡 ； 線粒體自噬 ； 非結構蛋白5A ； 病毒持續性

並列摘要

Hepatitis C virus (HCV) infection is a major public health problem globally infecting more than 170 million people. The virus predisposes the majority of its victims to end-stage liver diseases including hepatocellular carcinoma (HCC) which is the third leading cause of cancer-related deaths worldwide. HCV non-structural protein (NS5A) is a regulator of the viral replication and assembly which has been documented to modulate cellular physiological pathways such as induction of reactive oxygen species (ROS) and deregulation of calcium homeostasis, as well as interfering with the interferon response. Mitophagy is a selective form of autophagy, targeting damaged mitochondria for lysosomal degradation. Although HCV infection has been previously shown to trigger alteration in mitochondrial dynamics thereby leading to the induction of mitophagy, the precise underlying mechanism, the effector protein responsible, and the implication of mitophagy in the viral pathogenesis remain unclear. Interestingly, the NS5A protein has been observed to take part in the induction of autophagy-related events. Herein, we demonstrate that the HCV NS5A protein plays a key function in the induction of mitophagy, particularly at the mitochondria level, leading to perturbation of mitochondria-associated physiological processes as means to confer viral persistence. Specifically, overexpression of HCV NS5A in the hepatoma cells triggered the induction of mitophagy with attributes of mitochondrial fragmentation and Parkin translocation to the mitochondria as demonstrated by western blotting and confocal microscopy. Evaluation of cellular cytotoxicity under the influence of NS5A with mitophagy induction indicated no difference in cell viability, but a significant enhancement in proliferation rate when NS5A protein is present. These results suggest that HCV NS5A protein triggers mitophagy and perturb the mitochondrial dynamics to promote cell growth, contrary to triggering apoptosis as with usual disruption of the mitochondria, and thereby contributing to the persistence of HCV-infected cells. Results from this study may have implication in broadening our understanding of HCV disease pathogenesis and provide therapeutic strategies for the management of HCV infection-associated diseases.

並列關鍵字

HCV, mitochondrial dynamics ； mitophagy ； NS5A ； Parkin ； viral persistence

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