title: Interactions Between Hepatitis C Virus and Mitochondria: Impact on Pathogenesis and Innate Immunity.
abstract: Hepatitis C virus (HCV) causes a persistent chronic infection of hepatocytes resulting in progressive fibrosis and carcinogenesis. Abnormalities in mitochondria are prominent features of clinical disease where ultrastructural changes, alterations in electron transport, and excess reactive oxygen species (ROS) production occur. These mitochondrial abnormalities correlate with disease severity and resolve with viral eradication. Multiple viral proteins, particularly core and NS3/4a bind to mitochondria. The core and NS5a proteins primarily cause ER stress, ER Ca2+release and enhance direct transfer of Ca2+from ER to mitochondria. This results in electron transport changes, increased ROS production and sensitivity to mitochondrial permeability transition and cell death. The viral protease, NS3/4a, binds to mitochondria as well where it cleaves an important signaling adapter, MAVS, thus preventing viral clearance by endogenous interferon production. This review discusses the mechanisms by which HCV causes mitochondrial changes and consequences of these for disease.
authors: Liver Center and Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160.
authors: Ting
authors: T
authors: Wang
authors: Steven A
authors: SA
authors: Weinman
keywords: Antioxidants; Calcium; ER stress; Electron transport; HCV core protein; Hepatitis C virus; Innate immunity; Interferon; Liver disease; Mitochondria associated membrane; Mitochondrial antiviral signaling protein; Mitochondrial calcium uniporter; Mitophagy; Oxidative stress; Pathobiology; ROS; Reactive oxygen species
references: J Hepatol. 1999 May;30(5):774-82
references: 10365801
references: PLoS Pathog. 2013 Mar;9(3):e1003285
references: 23555273
references: Semin Liver Dis. 2009 May;29(2):188-99
references: 19387918
references: J Interferon Cytokine Res. 2009 Sep;29(9):489-98
references: 19708811
references: PLoS One. 2012;7(5):e37700
references: 22662193
references: J Viral Hepat. 2010 Nov;17(11):784-93
references: 20002299
references: Am J Gastroenterol. 1999 Aug;94(8):2198-205
references: 10445550
references: J Virol. 2008 Nov;82(21):10375-85
references: 18768989
references: Hepatology. 1997 Jul;26(1):135-42
references: 9214462
references: J Hepatol. 1999 Nov;31(5):808-14
references: 10580577
references: J Hepatol. 2009 May;50(5):872-82
references: 19303156
references: Annu Rev Pharmacol Toxicol. 2013;53:427-49
references: 23140245
references: Adv Cancer Res. 2005;94:87-142
references: 16096000
references: Liver Int. 2011 Nov;31(10):1432-48
references: 22093324
references: Viruses. 2011 Nov;3(11):2238-54
references: 22163343
references: J Biol Chem. 2001 Jun 22;276(25):23077-83
references: 11304537
references: Gastroenterology. 2005 Jan;128(1):96-107
references: 15633127
references: J Med Virol. 2010 May;82(5):776-92
references: 20336713
references: Am J Pathol. 2014 Nov;184(11):3026-39
references: 25244949
references: J Virol. 2009 Dec;83(24):12934-46
references: 19812163
references: Biochem J. 2004 Mar 15;378(Pt 3):919-28
references: 14670077
references: Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9599-604
references: 11481452
references: Hepatology. 2008 Oct;48(4):1336-41
references: 18821593
references: Toxicol Appl Pharmacol. 2010 Apr 1;244(1):57-65
references: 20122946
references: J Biol Chem. 2004 Nov 12;279(46):47939-51
references: 15347644
references: J Biol Chem. 2011 Mar 18;286(11):8941-51
references: 21216956
references: PLoS Pathog. 2010 Jan;6(1):e1000719
references: 20062526
references: Cell. 2005 Sep 9;122(5):669-82
references: 16125763
references: J Virol. 2004 Aug;78(15):7958-68
references: 15254168
references: Antioxid Redox Signal. 2004 Feb;6(1):19-24
references: 14713333
references: Nature. 2011 Jun 19;476(7360):336-40
references: 21685888
references: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18666-70
references: 18003907
references: Biochim Biophys Acta. 2009 May;1787(5):539-46
references: 19094961
references: N Engl J Med. 1989 Nov 30;321(22):1494-500
references: 2509915
references: J Virol. 2005 Jan;79(2):1271-81
references: 15613354
references: Cancer Res. 2001 Jun 1;61(11):4365-70
references: 11389061
references: J Gen Virol. 2013 Jul;94(Pt 7):1528-1534
references: 23580428
references: FASEB J. 2007 Aug;21(10):2474-85
references: 17392480
references: PLoS One. 2011;6(9):e24957
references: 21931870
references: Cancer Detect Prev. 2004;28(6):385-91
references: 15582261
references: Mol Cells. 2012 Jul;34(1):7-13
references: 22610403
references: J Hepatol. 2013 Mar;58(3):564-74
references: 23063572
references: J Gen Virol. 2010 Mar;91(Pt 3):681-690
references: 19889935
references: Oncogene. 2005 Jul 21;24(31):4921-33
references: 15897896
references: Free Radic Res. 2002 Sep;36(9):939-48
references: 12448819
references: Biochem Soc Trans. 2011 Apr;39(2):532-6
references: 21428934
references: Gastroenterology. 2006 Jun;130(7):2087-98
references: 16762631
references: J Hepatol. 2008 Mar;48(3):399-406
references: 18164507
references: Nat Rev Microbiol. 2007 Jun;5(6):453-63
references: 17487147
references: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1200-5
references: 9037030
references: Nat Rev Mol Cell Biol. 2012 Sep;13(9):566-78
references: 22850819
references: J Virol. 2006 Jul;80(14):7199-207
references: 16809325
references: Viruses. 2011 Aug;3(8):1342-57
references: 21994783
references: Can J Gastroenterol. 2003 Nov;17(11):644-50
references: 14631465
references: Front Biosci (Landmark Ed). 2011 Jan 01;16:608-18
references: 21196192
references: Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14590-5
references: 21844353
references: J Virol. 2005 Dec;79(24):15525-36
references: 16306623
references: RNA Biol. 2011 Mar-Apr;8(2):258-69
references: 21593584
references: J Hepatol. 2000 Oct;33(4):616-22
references: 11059866
references: Eur J Clin Invest. 2001 Jan;31(1):54-63
references: 11168439
references: Gastroenterology. 2008 Jan;134(1):226-38
references: 18166355
references: Hepatology. 2014 Jan;59(1):58-70
references: 23857333
references: J Virol. 2002 Aug;76(15):7453-9
references: 12097557
references: Biol Chem. 2012 Jul;393(7):547-64
references: 22944659
references: Hepatol Res. 2006 Feb;34(2):65-73
references: 16364681
references: Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17717-22
references: 16301520
references: PLoS One. 2011;6(12):e28551
references: 22164304
references: Ann Surg Oncol. 2007 Mar;14(3):1182-90
references: 17195915
references: J Hepatol. 2001 Apr;34(4):587-92
references: 11394660
references: Hepatology. 2010 Jul;52(1):47-59
references: 20578128
references: Viruses. 2012 Oct 19;4(10):2251-90
references: 23202463
references: J Gastroenterol Hepatol. 2006 Oct;21 Suppl 3:S34-7
references: 16958669
references: Free Radic Biol Med. 1998 May;24(7-8):1235-41
references: 9626579
references: J Hepatol. 2002 Jun;36(6):805-11
references: 12044532
references: Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1664-73
references: 16356128
references: Biochem Soc Trans. 2009 Oct;37(Pt 5):986-90
references: 19754437
references: Biochem Biophys Res Commun. 2008 Apr 11;368(3):593-9
references: 18258181
references: Am J Gastroenterol. 2002 Oct;97(10):2634-9
references: 12385452
references: Hepatology. 2007 Jul;46(1):58-65
references: 17567832
references: J Hepatol. 2010 Aug;53(2):245-51
references: 20537752
references: Lancet Infect Dis. 2005 Sep;5(9):558-67
references: 16122679
references: Hepatology. 2004 Jan;39(1):81-9
references: 14752826
references: Hepatol Res. 2008 Apr;38(4):348-53
references: 18021228
references: Mol Syst Biol. 2008;4:230
references: 18985028
references: J Biol Chem. 2005 Nov 11;280(45):37481-8
references: 16150732
references: Virol J. 2011 Sep 06;8:424
references: 21896168
references: EMBO Rep. 2011 Sep 01;12(9):901-10
references: 21799518
references: Gastroenterology. 2002 Feb;122(2):366-75
references: 11832451
references: Trends Microbiol. 2005 Apr;13(4):159-63
references: 15817385
references: Free Radic Biol Med. 2006 Nov 1;41(9):1488-98
references: 17023276
references: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G847-51
references: 16603728
references: Science. 1989 Apr 21;244(4902):359-62
references: 2523562
references: Hepatology. 2009 Aug;50(2):378-86
references: 19591124
references: J Virol. 2003 May;77(9):5487-92
references: 12692249
references: Liver Int. 2008 Sep;28(8):1158-66
references: 18410284
references: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):6001-6
references: 16585524
references: Am J Gastroenterol. 2008 Jan;103(1):147-53
references: 18184121
references: PLoS Pathog. 2009 Feb;5(2):e1000291
references: 19242562
references: J Virol. 2012 Mar;86(6):3112-20
references: 22238314
references: J Gen Virol. 2006 Jul;87(Pt 7):1935-1945
references: 16760395