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Mitochondrial dynamics in hepatitis B and C virus persistent viral infections (575.9)
Author(s) -
Kim SeongJun,
Syed Gulam,
Khan Mohsin,
Sohail Muhammad,
Siddiqui Aleem
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.575.9
Subject(s) - mitochondrial fission , mitophagy , parkin , biology , pink1 , mitochondrion , dnm1l , mfn1 , microbiology and biotechnology , mfn2 , virology , mitochondrial fusion , apoptosis , mitochondrial dna , autophagy , biochemistry , medicine , disease , pathology , parkinson's disease , gene
Human hepatitis B and C virus (HBV and HCV) infections are the leading cause of chronic liver disease. Mitochondrial liver injury is associated with HBV and HCV infections. The objective of our studies is to demonstrate viral involvement in mitochondrial dynamics. Results: We show here that both HBV and HCV triggered mitochondrial fission and mitophagy. Both viruses induced perinuclear clustering of mitochondria, stimulated the gene expression of dynamin‐related protein 1 (Drp1) and its mitochondrial receptor, mitochondrial fission factor (Mff). Both viruses promoted Drp1 phosphorylation at Ser616 and its mitochondrial translocation followed by mitochondrial fission. Both viruses also stimulated the expression of Parkin, PINK1, and LC3B and induced Parkin recruitment to the mitochondria followed by mitophagy. Upon translocation to mitochondria, E3 ubiquitin ligase Parkin was self‐ubiquitinated and facilitated the ubiquitination and degradation of its substrate Mitofusin 2, a mediator of mitochondrial fusion. Interference of virus‐induced aberrant mitochondrial fission and mitophagy by silencing Drp1 and Parkin suppressed viral assembly and secretion with a concomitant decrease in cellular glycolysis and ATP levels. More importantly, it caused significant increase in apoptotic signaling evidenced by a notable increase in release of cytochrome C from the mitochondria, caspase‐3/7 activity, cleavage of poly(ADP‐ribose) polymerase (PARP) and caspase‐3, and apoptotic cell death. Conclusions: Aberrant mitochondrial dynamics induced by HBV and HCV infections attenuates apoptosis of infected hepatocytes. These events may also contribute to the persistent viral infection. Grant Funding Source : NIH DK 077704