title: Hepatitis C virus induces the mitochondrial translocation of Parkin and subsequent mitophagy.
abstract: Hepatitis C Virus (HCV) induces intracellular events that trigger mitochondrial dysfunction and promote host metabolic alterations. Here, we investigated selective autophagic degradation of mitochondria (mitophagy) in HCV-infected cells. HCV infection stimulated Parkin and PINK1 gene expression, induced perinuclear clustering of mitochondria, and promoted mitochondrial translocation of Parkin, an initial event in mitophagy. Liver tissues from chronic HCV patients also exhibited notable levels of Parkin induction. Using multiple strategies involving confocal and electron microscopy, we demonstrated that HCV-infected cells display greater number of mitophagosomes and mitophagolysosomes compared to uninfected cells. HCV-induced mitophagy was evidenced by the colocalization of LC3 puncta with Parkin-associated mitochondria and lysosomes. Ultrastructural analysis by electron microscopy and immunoelectron microscopy also displayed engulfment of damaged mitochondria in double membrane vesicles in HCV-infected cells. The HCV-induced mitophagy occurred irrespective of genotypic differences. Silencing Parkin and PINK1 hindered HCV replication suggesting the functional relevance of mitophagy in HCV propagation. HCV-mediated decline of mitochondrial complex I enzyme activity was rescued by chemical inhibition of mitophagy or by Parkin silencing. Overall our results suggest that HCV induces Parkin-dependent mitophagy, which may have significant contribution in mitochondrial liver injury associated with chronic hepatitis C.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Seong-Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Gulam H
authors.initials: GH
authors.lastname: Syed
authors.forename: Aleem
authors.initials: A
authors.lastname: Siddiqui
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000821:virology; D063306:Mitophagy / Q000502:physiology*; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure / Q000821:virology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
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