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Clue for hepatitis C survival, avoids elimination, potential therapeutic target - 'Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence'
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Download the PDF here
Download the PDF here
(integrates into mitochondria....."result of the failure to mount an efficient immune response to eliminate infected hepatocytes.....Our findings implicate the mitochondrial quality control pathway as a potential therapeutic target against HCV infection and associated liver disease pathogenesis")
http://www.digitaljournal.com/science/clue-for-hepatitis-c-survival/article/381437
Scientists have identified why people with the hepatitis C virus get liver disease and why the virus is able to persist in the body for so long. The answer is that the virus attacks the liver cells' energy centers.
The hepatitis C virus appears attempt at attacking a liver cell structure called the mitochondria. Mitochondria are found in every cell in the human body; they are responsible for creating more than 90 percent of the energy needed by the body to sustain life and support growth
By attacking the mitochondria, the virus appears to dismantle the cell's innate ability to fight infection. Cells recognize the damage and respond to it by recruiting proteins that tell the mitochondria to eliminate the damaged area, but the repair process ends up helping the virus to replicate and infect other cells.
Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV). Chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure or liver cancer. The virus is spread is spread primarily by blood-to-blood contact associated with intravenous drug use, poorly sterilized medical equipment, and transfusions.
The new research suggests that suggests that mitochondrial operations could be a therapeutic target against hepatitis C, the leading cause of liver transplants and a major cause of liver cancer in the U.S.
The study was carried out at the University of California, San Diego School of Medicine. The findings have been published in the journal Proceedings of the National Academy of Sciences, in a paper titled "Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence".
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Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence
Proceedings of the National Academy of Sciences - PNAS Early Edition published ahead of print April 14
Seong-Jun Kima,1, Gulam H. Syeda,1, Mohsin Khana, Wei-Wei Chiua, Muhammad A. Sohailb, Robert G. Gishc, and Aleem Siddiquia,2
aDivision of Infectious Diseases and bDivision of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093; and cHepatitis B Foundation, Doylestown, PA 18901
Edited by Michael Gale, Jr., University of Washington School of Medicine, Seattle, WA, and accepted by the Editorial Board March 18, 2014 (received for
review November 8, 2013)
"Taken together, these results suggest that HCV-induced mitochondrial fission both affects HCV secretion and contributes in part to the evasion of the innate immune system.......
.......The primary cause of persistent HCV infection is a result of the failure to mount an efficient immune response to eliminate infected hepatocytes (2). However, HCV-induced aberrant mitochondrial dynamics may also contribute to the viral persistence by attenuating apoptosis of infected cells. A similar strategy of perturbation of mitochondrial dynamics and attenuation of apoptosis is also used by hepatitis B virus (29). Our findings implicate the
mitochondrial quality control pathway as a potential therapeutic target against HCV infection and associated liver disease pathogenesis......
.......Mitochondrial depolarization, membrane permeabilization, and swelling are common occurrences in HCV infection (36). Hence, survival of HCV-infected cells is probably dependent on their ability to clear dysfunctional mitochondria. Mitochondrial quality control maintains healthy mitochondria and cell viability. Malfunction of mitochondrial quality control results in the accumulation and ATP levels (32).......
.......Mitochondrial fission and mitophagy are the key determinants of mitochondrial quality control, and HCV modulates these key processes in the adaptation to cellular physiological perturbations associated with infection to promote viral persistence."
Significance
Persistent hepatitis C virus (HCV) infection is associated with mitochondrial liver injury. Mitochondrial quality control is established as a physiological adaptation to mitochondrial injury. This study provides a new insight into how HCV disrupts mitochondrial dynamics and evades apoptosis and innate immunity to sustain persistent viral infection. HCV promoted dynamin-related protein 1-mediated mitochondrial fission, followed by mitophagy. Interference of HCV-induced mitochondrial fission and mitophagy led to the suppression of virus secretion, a decrease in glycolysis and ATP generation, an increase in interferon synthesis, and an increase in apoptotic death of infected cells via enhanced apoptotic signaling. These observations implicate the functional relevance of altered mitochondrial dynamics in the pathogenesis of chronic liver disease associated with HCV infection.
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.
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