title: Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence.
abstract: Mitochondrial dynamics is crucial for the regulation of cell homeostasis. Our recent findings suggest that hepatitis C virus (HCV) promotes Parkin-mediated elimination of damaged mitochondria (mitophagy). Here we show that HCV perturbs mitochondrial dynamics by promoting mitochondrial fission followed by mitophagy, which attenuates HCV-induced apoptosis. HCV infection stimulated expression of dynamin-related protein 1 (Drp1) and its mitochondrial receptor, mitochondrial fission factor. HCV further induced the phosphorylation of Drp1 (Ser616) and caused its subsequent translocation to the mitochondria, followed by mitophagy. Interference of HCV-induced mitochondrial fission and mitophagy by Drp1 silencing suppressed HCV secretion, with a concomitant decrease in cellular glycolysis and ATP levels, as well as enhanced innate immune signaling. More importantly, silencing Drp1 or Parkin caused significant increase in apoptotic signaling, evidenced by increased cytochrome C release from mitochondria, caspase 3 activity, and cleavage of poly(ADP-ribose) polymerase. These results suggest that HCV-induced mitochondrial fission and mitophagy serve to attenuate apoptosis and may contribute to persistent HCV infection.
authors.affiliation: Division of Infectious Diseases and Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Seong-Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Gulam H
authors.initials: GH
authors.lastname: Syed
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Chiu
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Sohail
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gish
authors.forename: Aleem
authors.initials: A
authors.lastname: Siddiqui
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor; D034281:Dynamins / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D021381:Protein Transport
chemical_list: D008565:Membrane Proteins; C533267:Mff protein, human; D024101:Mitochondrial Proteins; D010768:Phosphoserine; D034281:Dynamins
keywords: HCV persistence; autophagy; innate immunity
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