title: Hepatitis B virus disrupts mitochondrial dynamics: induces fission and mitophagy to attenuate apoptosis.
abstract: Human hepatitis B virus (HBV) causes chronic hepatitis and is associated with the development of hepatocellular carcinoma. HBV infection alters mitochondrial metabolism. The selective removal of damaged mitochondria is essential for the maintenance of mitochondrial and cellular homeostasis. Here, we report that HBV shifts the balance of mitochondrial dynamics toward fission and mitophagy to attenuate the virus-induced apoptosis. HBV induced perinuclear clustering of mitochondria and triggered mitochondrial translocation of the dynamin-related protein (Drp1) by stimulating its phosphorylation at Ser616, leading to mitochondrial fission. HBV also stimulated the gene expression of Parkin, PINK1, and LC3B and induced Parkin recruitment to the mitochondria. Upon translocation to mitochondria, Parkin, an E3 ubiquitin ligase, underwent self-ubiquitination and facilitated the ubiquitination and degradation of its substrate Mitofusin 2 (Mfn2), a mediator of mitochondrial fusion. In addition to conventional immunofluorescence, a sensitive dual fluorescence reporter expressing mito-mRFP-EGFP fused in-frame to a mitochondrial targeting sequence was employed to observe the completion of the mitophagic process by delivery of the engulfed mitochondria to lysosomes for degradation. Furthermore, we demonstrate that viral HBx protein plays a central role in promoting aberrant mitochondrial dynamics either when expressed alone or in the context of viral genome. Perturbing mitophagy by silencing Parkin led to enhanced apoptotic signaling, suggesting that HBV-induced mitochondrial fission and mitophagy promote cell survival and possibly viral persistence. Altered mitochondrial dynamics associated with HBV infection may contribute to mitochondrial injury and liver disease pathogenesis.
authors: Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors: Seong-Jun
authors: SJ
authors: Kim
authors: Mohsin
authors: M
authors: Khan
authors: Jun
authors: J
authors: Quan
authors: Andreas
authors: A
authors: Till
authors: Suresh
authors: S
authors: Subramani
authors: Aleem
authors: A
authors: Siddiqui
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000235:genetics / Q000473:pathology / Q000821:virology*; D006515:Hepatitis B virus / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000235:genetics; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy / Q000235:genetics; D010588:Phagosomes / Q000821:virology; D021381:Protein Transport; D015534:Trans-Activators / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins