Hepatitis C virus core protein suppresses mitophagy by interacting with parkin in the context of mitochondrial depolarization

Yuichi Hara, Izumi Yanatori, Masanori Ikeda, Emi Kiyokage, Sohji Nishina, Yasuyuki Tomiyama, Kazunori Toida, Fumio Kishi, Nobuyuki Kato, Michio Imamura, Kazuaki Chayama, Keisuke Hino

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26 Citations (Scopus)

Abstract

Hepatitis C virus (HCV) causes mitochondrial injury and oxidative stress, and impaired mitochondria are selectively eliminated through autophagy-dependent degradation (mitophagy). We investigated whether HCV affects mitophagy in terms of mitochondrial quality control. The effect of HCV on mitophagy was examined using HCV-Japanese fulminant hepatitis-1-infected cells and the uncoupling reagent carbonyl cyanide m-chlorophenylhydrazone as a mitophagy inducer. In addition, liver cells from transgenic mice expressing the HCV polyprotein and human hepatocyte chimeric mice were examined for mitophagy. Translocation of the E3 ubiquitin ligase Parkin to the mitochondria was impaired without a reduction of pentaerythritol tetranitrate-induced kinase 1 activity in the presence of HCV infection both in vitro and in vivo. Coimmunoprecipitation assays revealed that Parkin associated with the HCV core protein. Furthermore, a Yeast Two-Hybrid assay identified a specific interaction between the HCV core protein and an N-terminal Parkin fragment. Silencing Parkin suppressed HCV core protein expression, suggesting a functional role for the interaction between the HCV core protein and Parkin in HCV propagation. The suppressed Parkin translocation to the mitochondria inhibited mitochondrial ubiquitination, decreased the number of mitochondria sequestered in isolation membranes, and reduced autophagic degradation activity. Through a direct interaction with Parkin, the HCV core protein suppressed mitophagy by inhibiting Parkin translocation to the mitochondria. This inhibition may amplify and sustain HCV-induced mitochondrial injury.

Original languageEnglish
Pages (from-to)3026-3039
Number of pages14
JournalAmerican Journal of Pathology
Volume184
Issue number11
DOIs
Publication statusPublished - Nov 1 2014

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Hara, Y., Yanatori, I., Ikeda, M., Kiyokage, E., Nishina, S., Tomiyama, Y., Toida, K., Kishi, F., Kato, N., Imamura, M., Chayama, K., & Hino, K. (2014). Hepatitis C virus core protein suppresses mitophagy by interacting with parkin in the context of mitochondrial depolarization. American Journal of Pathology, 184(11), 3026-3039. https://doi.org/10.1016/j.ajpath.2014.07.024