review article viruses as modulators of mitochondrial...

Hindawi Publishing CorporationAdvances in VirologyVolume 2013 Article ID 738794 17 pageshttpdxdoiorg1011552013738794

Review ArticleViruses as Modulators of Mitochondrial Functions

Sanjeev K Anand12 and Suresh K Tikoo123

1 Vaccine amp Infection Disease Organization-International Vaccine Center (VIDO-InterVac)University of Saskatchewan 120 Veterinary Road Saskatoon SK Canada S7E 5E3

2Veterinary Microbiology University of Saskatchewan 120 Veterinary Road Saskatoon SK Canada S7E 5E33 School of Public Health University of Saskatchewan 120 Veterinary Road Saskatoon SK Canada S7E 5E3

Correspondence should be addressed to Suresh K Tikoo sureshtikusaskca

Received 26 June 2013 Accepted 30 August 2013

Academic Editor Michael Bukrinsky

Copyright copy 2013 S K Anand and S K TikooThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Mitochondria are multifunctional organelles with diverse roles including energy production and distribution apoptosis elicitinghost immune response and causing diseases and aging Mitochondria-mediated immune responses might be an evolutionaryadaptation bywhichmitochondriamight have prevented the entry of invadingmicroorganisms thus establishing themas an integralpart of the cell This makes them a target for all the invading pathogens including viruses Viruses either induce or inhibit variousmitochondrial processes in a highly specific manner so that they can replicate and produce progeny Some viruses encode the Bcl2homologues to counter the proapoptotic functions of the cellular and mitochondrial proteins Others modulate the permeabilitytransition pore and either prevent or induce the release of the apoptotic proteins from themitochondria Viruses likeHerpes simplexvirus 1 deplete the host mitochondrial DNA and some like human immunodeficiency virus hijack the host mitochondrial proteinsto function fully inside the host cell All these processes involve the participation of cellular proteins mitochondrial proteins andvirus specific proteinsThis review will summarize the strategies employed by viruses to utilize cellular mitochondria for successfulmultiplication and production of progeny virus

1 Introduction

11 Mitochondria Mitochondria are cellular organellesfound in the cytoplasm of almost all eukaryotic cells One oftheir important functions is to produce and provide energy tothe cell in the form of ATP which help in propermaintenanceof the cellular processes thus making them indispensablefor the cell Besides acting as a powerhouse for the cell theyact as a common platform for the execution of a variety ofcellular functions in normal or microorganism infected cellsMitochondria have been implicated in aging [1 2] apoptosis[3ndash7] the regulation of cell metabolism [4 8] cell-cyclecontrol [9ndash11] development of the cell [12ndash14] antiviralresponses [15] signal transduction [16] and diseases [17ndash20]

Although all mitochondria have the same architecturethey vary greatly in shape and size The mitochondria arecomposed of outer mitochondrial membrane inner mito-chondrial membrane intermembrane space (space betweenouter and inner membrane) and matrix (space withininner mitochondrial membrane) The outer membrane is a

smooth phospholipid bilayer with different types of proteinsimbedded in it [21] The most important of them are theporins which freely allow the transport (export and import)of the molecules (proteins ions nutrients and ATP) lessthan 10 kDa across the membranes The outer membranesurrounds the inner membrane creating an intermembranespace that contains molecules such as Cyt-C SMACDiabloand endonuclease G It also acts as a buffer zone betweenthe outer membrane and the inner membrane of mito-chondria The inner membrane is highly convoluted intostructures called cristae which increases the surface area ofthemembrane and are the seats of respiratory complexesTheinner membrane of mitochondria allows the free transport ofoxygen and carbon dioxide The movement of water throughmembranes is suggested to be controlled by aquaporinschannel protein [22 23] though a report suggested otherwise[24]Thematrix contains enzymes for the aerobic respirationdissolved oxygen water carbon dioxide and the recyclableintermediates that serve as energy shuttles and perform otherfunctions

2 Advances in Virology

Mitochondria contain a single 16 kb circular DNAgenome which codes for 13 proteins (mostly subunits of res-piratory chains I II IV and V) 22 mitochondrial tRNAs and2 rRNAs [25 26]Themitochondrial genome is not enveloped(like nuclear envelop) contains few introns and does notfollow universal genetic code [27] Although the majority ofthe mitochondrial proteins are encoded by nuclear DNA andimported into the mitochondria (reviewed by [21 28ndash31])mitochondria synthesize few proteins that are essential fortheir respiratory function [1 27]

Proteins destined to mitochondria have either internallylocalized [28] or amino terminal localized [21] presequencesknown as mitochondriamatrix localization signals (MLS)which can be 10ndash80 amino acid long with predominantlypositively charged amino acids The combination of thesepresequences with adjacent regions determines the local-ization of a protein in respective mitochondrial compart-ments The outer mitochondrial membrane contains twomajor translocators namely (a) the translocase of outermembrane (TOM) 40 which functions as an entry gate formost mitochondrial proteins with MLS and (b) sorting andassembly machinery (SAM) or translocase of 120573-barrel (TOB)protein which is a specialized insertion machinery for beta-barrel membrane proteins [32] Once proteins pass throughthe outer membrane they are recruited by presequencetranslocase-associated motor (PAM) to the translocase of theinner mitochondrial membrane (TIM) 23 complexes whichmediates the import of proteins to the matrix Finally thepresequences are cleaved in matrix and proteins are modifiedto their tertiary structure and rendered functional [30]

12 Viruses Viruses are acellular obligate intracellularmicro-organisms that infect the living cellsorganisms and are theonly exception to cell theory proposed by Schleiden andSchwann in 18381839 [33] The viruses have an outer proteincapsid and a nucleic acid core Usually the viral nucleic acidscan be either DNA (double or single stranded) or RNA (+or minus sense single stranded or double stranded RNA) Someof the viruses are covered with an envelope embedded withglycoproteinsThe viruses have long been associated with theliving organisms and it was in the later part of the centurythat their relationship with various cellular organelles wasstudied in detail In order to survive and replicate in the cellviruses need to take control of the various cellular organellesinvolved in defense and immune processesThey also requireenergy to replicate and escape from the cell Once inside thehost cell they modulate various cellular signal pathways andorganelles including mitochondria and use them for theirown survival and replication This review summarizes thefunctions of mitochondria and how viruses modulate them(Figure 1)

2 Viruses Regulate Ca2+

Homeostasis in Host Cells

21 Ca2+ Homeostasis Ca2+ is one of the most abundant andversatile elements in the cell and acts as a second messen-ger to regulate many cellular processes [34] Earlier outermembrane of mitochondria was thought to be permeable to

Ca2+ but recent studies suggest that the outer membranecontains voltage-dependent anion channels (VDAC) havingCa2+ binding domains which regulate the entry of Ca2+into the mitochondrial intermembrane space [35ndash37] Theinflux of Ca2+ through the inner membrane is regulatedby the mitochondrial Ca2+ uniporter (MCU) which is ahighly selective Ca2+ channel that regulates the Ca2+ uptakebased onmitochondrialmembrane potential (MMP)Thenetmovement of charge due to Ca2+ uptake is directly propor-tional to the decrease ofMMP [38] A secondmechanism thathelps in Ca2+ movement across the mitochondria membraneis called ldquorapid moderdquo uptake mechanism (RaM) [39] In thisprocess Ca2+ transports across themitochondrial membraneby exchange with Na+ which in turn depends upon itsexchange with H+ ion and thus MMP This ion exchangeacross the mitochondrial membrane decreases MMP and isdependent on electron transport chain (ETC) for its mainte-nance A third mechanism involves IP

3R a Ca2+ channel in

endoplasmic reticulum IP3R is connected to mitochondrial

VDAC through a glucose regulating protein 75 (GRP75)This junction regulatesfacilitates Ca2+ exchange from IP

3R

to VDAC [40]Ca2+ efflux mechanism is regulated by the permeability

transition pore (PTP) The PTP is assembled in the mito-chondrial inner and outer membranes [41 42] with Ca2+binding sites on the matrix side of the inner membrane ThePTP regulates the mitochondrial Ca2+ release by a highlyregulated ldquoFlickeringrdquo mechanism that controls the openingand closing of the pore [43] RaM works in sync withryanodine receptor (RyR) isoform 1 which is another veryimportant calcium release channel [44] Both RyR and RaMregulate the phenomenon of excitation-metabolism couplingin which cytosolic Ca2+ induced contraction is matchedby mitochondrial Ca2+ stimulation of ox-phos [45] How-ever mitochondrial Ca2+ overload can result in prolongedopening of the pore leading to pathology [46] AlthoughCa2+ is involved in the activation of many cellular processesincluding stimulation of the ATP synthase [47 48] allostericactivation of Krebs cycle enzymes [49 50] and the adeninenucleotide translocase (ANT) [51] the primary role of mito-chondrial Ca2+ is in the stimulation of ox-phos [52ndash54]Thusthe elevated mitochondrial Ca2+ results in up regulation ofthe entire ox-phos machinery which then results in fasterrespiratory chain activity and higher ATP output which canthen meet the cellular ATP demand Ca2+ also upregulatesother mitochondrial functions including activation of N-acetylglutamine synthetase to generate N-acetylglutamine[55] potent allosteric activation of carbamoyl-phosphatesynthetase and the urea cycle [56] Thus any perturbationinmitochondrial or cytosolic Ca2+ homeostasis has profoundimplications for cell functionMoreovermitochondrial Ca2+particularly at high concentrations experienced in pathologyappears to have several negative effects on mitochondrialfunctions [57]

22 Regulation by Viruses A number of viruses alter theCa2+regulatory activity of the cell for their survival Herpes

Advances in Virology 3

HCV)

IFNimmune regulation

Uniporter

Mitochondrial inner membrane permeability

(eg HIV HBV myxoma IA HTLV and WDSV)

RyR

(eg Polio Coxsackie and HCMV)

ER

II

IIIIV

I

ROS

Reactive oxygen species production

(eg EBV HBV and EMCV)

DNA damage cell death etc

VDAC

ER stress

MAVS

MAVS cleavage(eg HCV and

Cleavageat C-508

EndoGSmacDiabloCyt C

14-3-3

Bad

Caspase 9

Caspase 3

Apoptosis

ApoptosisInduction or prevention

(eg HAdV-5 HBV HB HIV etc)

Host mitochondrialDNA depletion

(eg HSV-1 and

FADD TRADDCaspase 8Pro

Caspase 8

Pre

ProCaspase 7

ProCaspase 7

Host mitochondrial protein hijack

(eg mimivirus)

Host mitochondrialprotein mimicry

(eg HIV and HCMV)

ATP

Cytoplasm

Nucleus

Mitochondria

Cell membrane

CARDCARDCARD

Endoplasmic reticulum

Cristae

Matrix

Outer mitochondrial membrane

Ca2+

IP3R

Ca2+ uptake via uniporterIncrease in

CARDCARDCARD

PTP

O2

GB virus)(eg HCVuarr HIVuarr and

HSVdarr)

Figure 1 Schematic diagram of cell showing mitochondria nucleus endoplasmic reticulum (ER) and cell membrane iCa2+ intracellularcalcium FADD Fas-associated protein with death domain TRADD tumor necrosis factor receptor type 1-associated death domain proteinPTP permeability transition pore VDAC voltage-dependent anion channel IP

3R inositol 145-trisphosphate receptor RyR ryanodine

receptor MAVS mitochondrial antiviral signaling I II III and IV are complex I to IV of electron transport chain O2

minus Superoxideradical Bad Bcl-2-associated death promoter ROS reactive oxygen species IFN interferon HCMV human cytomegalovirus HIVhuman immunodeficiency virus HSV herpes simplex virus HBV hepatitis B virus HTLV human T-lymphotropic virus IA influenzaA virus WDSV Walleye dermal sarcoma virus HCV hepatitis C virus HAdV human adenovirus-5 EBV Epstein-Barr virus and EMCVencephalomyocarditis virus

simplex type (HSV) 1 virus causes a gradual decline (65)in mitochondrial Ca2+ uptake at 12 hrs lytic cycle [58] whichhelps in virus replication Although mitochondrial Ca2+uptake keeps fluctuating throughout the course of a measlesvirus infection of cells the total amount of cellular Ca2+remains the same [58] indicating the tight control that thevirus exerts over the cellular processes during its life cycle

The core protein of hepatitis C virus (HCV) targetsmitochondria and increases Ca2+ [59 60] The NS5A proteinof HCV causes alterations in Ca2+ homeostasis [61ndash63] Bothof these proteins may be responsible for the pathogenesis ofliver disorders associated with HCV infection Even in thecells coinfected with HCV and human immunodeficiencyvirus (HIV) these viruses enhance the MCU activity causingcellular stress and apoptosis [59 64] The p7 protein of HCVforms porin-like structures [65] and causes Ca2+ influx tocytoplasm from storage organelles [66] These HCV proteinsdisturb the Ca2+ homeostasis at different stages of theinfection and thus help to enhance the survival of the cellInterestingly interaction of protein X of hepatitis B virus

(HBV) with VDAC causes the release of Ca2+ from storageorganelles mitochondriaendoplasmic reticulum (ER)golgiinto the cytoplasmic compartment which appears to helpvirus replication [67 68]

The Nef protein of HIV interacts with IP3R [69] and

induces an increase in cytosolic Ca2+ through promotion onT cell receptor-independent activation of the NFAT pathway[70] Activated NFAT in turn causes the low-amplitudeintracellular Ca2+ oscillation promoting the viral genetranscription and replication [71]

Ca2+ is an important factor for different stages of rotaviruslifecycle and for stability to rotavirus virion [72] The NSP4protein of rotavirus increases the cytosolic Ca2+ concentra-tion by activation of phospholipase C (PLC) and the resultantER Ca2+ depletion through IP

3R [73 74] This alteration in

Ca2+ homeostasis has been attributed to an increase in thepermeability of cell membrane [75] A decrease in cellularCa2+ concentrations toward the end of the life cycle has beenreported to enable rotavirus release from the cell [76]


The 2BC protein of poliovirus increases the intracellularCa2+ concentrations in the cells 4 hrs After infection whichis necessary for viral gene expression [77 78] Toward the endof the virus life cycle the release of Ca2+ from the lumen of ERthrough IP

3R and RyR channels causes accumulation of Ca2+

in mitochondria through uniporter and VDAC resulting inmitochondrial dysfunction and apoptosis [79] On the con-trary the 2B protein of Coxsackie virus decreases the mem-brane permeability by decreasing Ca2+ concentrations ininfected cells [80 81] due to its porin-like activity that resultsin Ca2+ efflux from the organelles Reduced protein traffick-ing and low Ca2+ concentration in golgi and ER favor theformation of viral replication complexes downregulate hostantiviral immune response and inhibit apoptosis [82 83]

Enteroviruses orchestrate the apoptotic process duringtheir life cycle to enhance its entry survival and releaseThe perturbation in cytoplasmic Ca2+ homeostasis at 2ndash4 hrspostinfection coincides with the inhibition of the apoptoticresponse that can be attributed to decrease in cytotoxic levelsof Ca2+ in the cell and the mitochondria This also providesthe virus with optimum conditions for the replication andprotein synthesis Finally a decrease in mitochondrial andother storage organelles (ER and golgi) Ca2+ levels causesan increase in cytosolic Ca2+ concentration leading to theformation of vesicles and cell death thus assisting in virusrelease [81 84 85]

The pUL37 times 1 protein of human cytomegalovirus(HCMV) localizes to mitochondria [86] and causes thetrafficking of Ca2+ from the ER to mitochondria at 4ndash6 hrsAfter infection [87] Active Ca2+ uptake by mitochondrioninduces the production of ATP and other Ca2+ dependentenzymes accelerating virus replication and a decrease inCa2+levels in the ER has antiapoptotic effects [88]

The 67K protein encoded by E3 region of HAdV-2localizes to ER and helps maintain ER Ca2+ homeostasis intransfected cells thus inhibiting apoptosis [89]

3 Viruses Cause Oxidative Stress in Host Cells

31 Electron Transport Chain Themitochondrial respiratorychain is the main and most significant source of reactiveoxygen species (RO) in the cell Superoxide (O

2

minus∙) is theprimary ROS produced bymitochondria In the normal statethere is little or no leakage of electrons between the complexesof the electron transport chain (ETC) However during stressconditions a small fraction of electrons leave complex III andreach complex IV [90] This premature electron leakage tooxygen results in the formation of two types of superoxidesnamely O

2

minus in its anionic form and HO2

minus in its protonatedform

Leakage of electrons takes place mainly from QO sitesof complex III which are situated immediately next tothe intermembrane space resulting in the release of super-oxides in either the matrix or the innermembrane spaceof the mitochondria [91ndash94] About 25ndash75 of the totalelectron leak through Complex III could account for thenet extramitochondrial superoxide release [95ndash97]Thus themain source of O

2

minus∙ in mitochondria is the ubisemiquinone

radical intermediate (QH∙) formed during the Q cycle at theQO site of complex III [98ndash100] Complex I is also a sourceof ROS but the mechanism of ROS generation is less clearRecent reports suggest that glutathionylation [101] or PKAmediated phosphorylation [101ndash103] of complex I can elevateROS generation Backward flow of electron from complex Ito complex II can also result in the production of ROS [99]

A variety of cellular defense mechanisms maintain thesteady state concentration of these oxidants at nontoxiclevels This delicate balance between ROS generation andmetabolism may be disrupted by various xenobiotics includ-ing viral proteins The main reason for generation of ROS invirus-infected cells is to limit the virus multiplication How-ever ROS also acts as a signal for various cellular pathwaysand the virus utilizes the chaos generated inside the cell forits replication

32 Viruses Induce Reactive Oxygen Species A number ofviruses cause oxidative stress to the host cells which directlyor indirectly helps them to survive Human-Adenovirus-(HAdV-) 5 has been reported to induce the rupture ofendosomal membrane upon infection resulting in the releaseof lysosomal cathepsins which prompt the production ofROS Cathepsins also induce the disruption of mitochondrialmembrane leading to the release of ROS from mitochondriathus causing the oxidative stress [104]

The core protein of HCV causes oxidative stress in thecell and alters apoptotic pathways [64 105ndash107] The E1 E2NS3 and core protein of HCV are potent ROS inducersand can cause host DNA damage independently [107 108]or mediated by nitric oxide (NO) thus aiding in virusreplication

The ROS is generated during HIV infection [64 109ndash111] H

2O2 an ROS generated during HIV infection strongly

induces HIV long terminal repeat (LTR) via NF-kappa Bactivation Impaired LTR activity ablates the LTR activationin response to ROS thus aiding in virus replication [112] HIValso causes extensive cellular damage due to increased ROSproduction and decreased cytosolic antioxidant production[113] Coinfection of HIV and HCV causes the hepaticfibrosis the progression of which is regulated through thegeneration of ROS in an NF-120581B dependent manner [113]

Epstein-Barr virus (EBV) causes increased oxidativestress in the host cells within 48 hrs During the lytic cycleindicating the role of ROS in virus release [114] Oxidativestress activates the EBV early gene BZLF-1 which causes thereactivation of EBV lytic cycle [114] This has been proposedto play an important role in the pathogenesis of EBV-associated diseases includingmalignant transformations [115116]

Interestingly HBV causes both an increase and a decreasein oxidative stress to enhance its survival in the host cells [117118] HBV induces strong activation of Nrf2ARE-regulatedgenes in vitro and in vivo through the activation of c-Raf andMEK by HBV protein X thus protecting the cells from HBVinduced oxidative stress and promoting establishment of theinfection [119] The protein X of HBV also induces the ROSmediated upregulation of Forkhead box class O4 (Foxo4)enhancing resistance to oxidative stress-induced cell death


[120] However reports also suggest that upon exposure tooxidative stress HBV protein X accelerates the loss of Mcl-1 protein via caspase-3 cascade thus inducing pro apoptoticeffects [118] Coinfection of HCV also causes the genotoxiceffects in peripheral blood lymphocytes due to increasedoxidative damage and decreasedMMP [121] It is possible thatcontradictory functions of protein X of HBV cold occur atdifferent stages of virus replication

Encephalomyocarditis virus (EMCV) causes oxidativestress in the cells during infection damaging the neuronswhich is an important process in the pathogenesis of EMCVinfection [122]

4 Viruses Regulate Mitochondrial MembranePotential in Host Cells

41 Mitochondrial Membrane Potential Membrane potential(MP) is the difference in voltage or electrical potentialbetween the interior and the exterior of a membrane Themembrane potential is generated either by electrical force(mutual attraction or repulsion between both positive ornegative) andor by diffusion of particles from high tolow concentrations The mitochondrial membrane potential(MMP) is an MP (cong 180mV) across the inner membraneof mitochondria which provides energy for the synthesis ofATP Movement of protons from complex I to V of electrontransport chain (ETC) located in the inner mitochondrialmembrane creates an electric potential across the innermembrane which is important for proper maintenance ofETC and ATP production Reported MMP values for mito-chondria (in vivo) differ from species to species and from oneorgan to another depending upon themitochondria functionprotein composition and the amount of oxidative phospho-rylation activity required in that part of the body [43]

The voltage dependent anionic channels (VDACs) alsoknown as mitochondrial porins form channels in the outermitochondrial membranes and act as primary pathway forthe movement of metabolites across the outer membrane[37 96 123ndash125] In addition a number of factors includingoxidative stress calcium overload and ATP depletion inducethe formation of nonspecific mitochondrial permeabilitytransition pores (MPTP) in the inner mitochondrial mem-brane which is also responsible for the maintenance of MMP[36 37 126] The outer membrane VDACs inner membraneadenine nucleotide translocase (ANT) [127] and cyclophilinD (CyP-D) in matrix are the structural elements of themitochondrial permeability transition pore (MPTP)

When open MPTP increases the permeability of theinner mitochondrial membrane to ions and solutes up to15 kDa which causes dissipation of the MMP and diffusionof solutes down their concentration gradients by a processknown as the permeability transition [128 129] The MPTPopening is followed by osmotic water flux passive swellingouter membrane rupture and release of proapoptotic factorsleading to the cell death [42 130] Because of the consequentdepletion of ATP and Ca2+ deregulation opening of theMPTP had been proposed to be a key element in determiningthe fate of the cell before a role for mitochondria in apoptosiswas proposed [129]

The MMP can be altered by a variety of stimuli includ-ing sudden burst of ROS [43 107] Ca2+ overload in themitochondria or the cell [48 57 131] andor by proteins ofinvading viruses [109 132 133] In general an increase ordecrease in MMP is related to the induction or preventionof apoptosis respectively Prevention of apoptosis duringearly stages of virus infection is a usual strategy employedby viruses to prevent host immune response and promotetheir replication On the contrary induction of apoptosisduring later stages of virus infection is a strategy used byviruses to release the progeny virions for dissemination to thesurrounding cells

42 Regulation by Viruses Many viral proteins alter mito-chondrial ion permeability andor membrane potential fortheir survival in the cell The p7 a hydrophobic integralmembrane [134] viroprotein [135] of HCV localizes to mito-chondria [66] and controlsmembrane permeability to cations[66 136] promoting cell survival for virus replication [135]

The R (Vpr) protein of HIV a small accessory proteinlocalizes to the mitochondria interacts with ANT modulatesMPTP and induces loss of MMP promoting release of CytoC [137] leading to cell death [138 139] The Tat protein ofHIV also modulates MPTP leading to the accumulation ofTat in mitochondria and induction of loss of MMP resultingin caspase dependent apoptosis [140]

The M11L protein of myxoma poxvirus localizes to themitochondria interacts with the mitochondrial peripheralbenzodiazepine receptor (PBR) and regulates MPTP [141]inhibiting MMP loss [142] and thus inhibiting inductionof apoptosis during viral infection [143] The FIL proteinof vaccinia virus downregulates proapoptotic Bcl-2 familyprotein Bak and inhibits the loss of the MMP and the releaseof Cyt-C [144 145] The crmASpi-2 protein of vacciniavirus a caspase 8 inhibitor modulatesMPTP thus preventingapoptosis [146]

The PB1-F2 protein of influenza A viruses localizes tothe mitochondria [147ndash150] and interacts with VDAC1 andANT3 [151] resulting in decreased MMP which induces therelease of proapoptotic proteins causing cell death Recentevidence shows that PB1-F2 is also able to form nonselectiveprotein channel pores resulting in the alteration ofmitochon-drial morphology dissipation of MMP and cell death [150]The M2 protein of influenza virus a viroprotein causes thealteration ofmitochondrialmorphology dissipation ofMMPand cell death (reviewed by [135])

The p13II an accessory protein encoded by x-II ORFof human T-lymphotropic virus (HTLV) a new member ofthe viroprotein family [152] localizes to the mitochondria ofinfected cells and increases the MMP leading to apoptosis[153] and mitochondrial swelling [153ndash155]

The Orf C protein of Walleye dermal sarcoma virus(WDSV) localizes to the mitochondria [156] and inducesperinuclear clustering of mitochondria and loss of MMP[156] leading to the release of proapoptotic factors thuscausing apoptosis

The 2B protein of Coxsackie virus decreases MMP bydecreasing the Ca2+ concentrations in infected cells [80 81]


5 Viruses Regulate Apoptosis

51 Apoptosis During the coevolution of viruses with theirhosts viruses have developed several strategies tomanipulatethe host cell machinery for their survival replication andrelease from the cell Viruses target the cellular apoptoticmachinery at critical stages of viral replication to meettheir ends [157 158] Depending upon the need a virusmay inhibit [159] or induce [160] apoptosis for the obviouspurpose of replication and spread respectively [158 159]Interference in mitochondrial function can cause either celldeath due to deregulation of the Ca2+ signaling pathwaysand ATP depletion or apoptosis due to regulation of Bcl-2family proteins Apoptosis is a programmed cell death [161]characterized by membrane blebbing condensation of thenucleus and cytoplasm and endonucleosomalDNA cleavageThe process starts as soon as the cell senses physiologicalor stress stimuli which disturbs the homeostasis of the cell[162 163] Apoptotic cell death can be considered as an innateresponse to limit the growth of microorganisms includingviruses attacking the cell

Two major pathways namely the extrinsic and theintrinsic are involved in triggering apoptosis [163 164] Theextrinsic pathway is mediated by signaling through deathreceptors like tumor necrosis factor or Fas ligand receptorcausing the assembly of death inducing signaling complex(DISC) with the recruitment of proteins like caspases leadingto the mitochondrial membrane permeabilization In theintrinsic pathway the signals act directly on themitochondrialeading to mitochondrial membrane permeabilization beforecaspases are activated causing the release of Cyt-C [165 166]which recruits APAF1 [167 168] resulting in direct activationof caspase 9 [35 169] Both the extrinsic and the intrinsicprocesses congregate at the activation of downstream effectorcaspases (ie caspase-3) [170]which is responsible for induc-ing the morphological changes observed in an apoptoticcell In addition to Cyt-C SmacDIABLO as well as cas-pase independent death effectors inducing factor (AIF) andendonuclease G [171ndash173] acts as an activator of the caspase

The B cell lymphoma- (Bcl-) 2 family of proteins tightlyregulate the apoptotic events involving the mitochondria[174 175] More than 20 mammalian Bcl-2 family pro-teins have been described to date [176 177] They havebeen classified by the presence of Bcl-2 homology (BH)domains arranged in the order BH4-BH3-BH2-BH1 andthe C-terminal hydrophobic transmembrane (TM) domainwhich anchors them to the outer mitochondrial membrane[178] The highly conserved BH1 and BH2 domains areresponsible for antiapoptotic activity and multimerization ofBcl-2 family proteinsThe BH3 domain is mainly responsiblefor proapoptotic activity and the less conserved BH4 domainis required for the antiapoptotic activities of Bcl-2 and Bcl-XLproteins [174 178] Most of the antiapoptotic proteins aremultidomain proteins which contain all four BH domains(BH1 to BH4) and a TM domain In contrast proapoptoticproteins are either multidomain proteins which containthree BH domains (BH1 to BH3) or single domain proteinswhich contain one domain (BH3) [158] The Bcl-2 proteinsregulate the MMP depending upon whether they belong to

the pro- or antiapoptotic branch of the family respectivelyThe MMP marks the dead end of apoptosis beyond whichcells are destined to die [125 166 179ndash183]

52 Regulation by Viruses Viruses encode homologs of Bcl-2(vBcl-2) proteins which can induce (pro-apototic) or prevent(antiapoptotic) apoptosis thus helping viruses to completetheir life cycle in the host cells [117 163 175] While the vBcl-2s and the cellular Bcl-2s share limited sequence homologytheir secondary structures are predicted to be quite similar[158 174 184] During primary infection interplay betweenvBcl-2 and other proteins enhances the lifespan of the hostcells resulting in efficient production of viral progeny andultimately spread of infection to the new cells It also favorsviral persistence in the cells by enabling the latently infectingviruses to make the transition to productive infection Thepathways and strategies used by viruses to induceinhibitapoptosis have been reviewed earlier [185]

Many viruses encode for the homologs of antiapoptoticBcl-2 proteins which preferentially localize to the mito-chondria and may interact with the other proapoptotic Baxhomologues The E1B19K encoded by human-adenovirus-(HAdV-) 5 contains BH1 and BH3-like domains and blocksTNF-alpha-mediated death signaling by inhibiting a formof Bax that interrupts the caspase activation downstream ofcaspase-8 and upstream of caspase-9 [186 187] Like HAdV-5 E1B19K [186] some viruses encode Bcl-2 homologueslacking BH4 domain which are thought to act by inhibitingproapoptotic members of Bcl-2 family proteins The FPV309protein encoded by fowl pox virus contains highly conservedBH1 and BH2-like domains and a cryptic BH3 domaininteracts with Bax protein and inhibits apoptosis [188] TheA179L protein encoded by African swine fever virus (ASFV)contains BH1 and BH2 domains and interacts with Bax-Bak proteins and inhibits apoptosis [189 190] The Bcl-2homolog (vBcl-2) encoded by Herpesvirus saimiri (HVS)contains BH3 and BH4-like domains and interacts with Baxthus stabilizing mitochondria against a variety of apoptoticstimuli preventing the cell death [191] The E4 ORF encodedby equine Herpesvirus-3 contains BH1 and BH2 domains[192] which may interact with Bax and be essential forantiapoptotic activity [193]

Viruses also encode homologs of proapoptotic Bcl-2proteins The HBV encodes protein X a vBcl-2 proteincontaining BH3 which localizes to the mitochondria andinteracts with VDACs inducing the loss of the MMP leadingto apoptosis [117 121 194 195] or interacts with Hsp60 andinduces apoptosis [196] In contrast another study revealedthe protective effects of HB-X in response to proapoptoticstimuli (Fas TNF and serum withdrawal) but not fromchemical apoptotic stimuli [197] The protein X of HBV isknown to stimulate NF120581B [198 199] SAPK [200 201] andPI3KPKB [202] to prevent apoptosis It is possible that thediverse functions of HBV protein X occur at different timesof virus replication cycle in the infected cells The BALF1protein encoded by EBV contains BH1 and BH4 domains[203] which interacts with the Bax-Bak proteins [192] andinhibits the antiapoptotic activity of the EBV BHRF1 and theKaposi Sarcoma virus (KSV) Bcl-2 protein both of which


contain BH1 and BH2 domains [204] and interact with BH3only proteins [205]

The effects of viral Bcl-2 homologues are thus apparentlycentered around mitochondria and include prevention orinduction of MMP loss The induction of MMP loss leads tothe release of Cyto C and other proapoptotic signals into thecytosol and activation of downstream caspases leading to thecell death and dissemination of viruses to neighbouring cellsfor further infection

Viruses encode proanti apoptotic proteins which shownohomology toBcl-2 proteins [158]TheE6protein of humanpapilloma virus (HPV) downregulates Bax signal upstreamof mitochondria [206 207] and prevents the release of CytoC AIF and Omi thus preventing apoptosis [208] This E6activity towards another Bcl2 family proapoptotic proteinBak is a key factor promoting the survival of HPV-infectedcells which in turn facilitates the completion of viral life cycle[207] Enterovirus (EV) 71 induces conformational changes inBax and increases its expression in cells following infectionand induces the activation of caspases 3 8 and PARPcausing caspase dependent apoptosis [209] On the contraryRubella viral capsid binds to Bax forms oligoheteromers andprevents the formation of pores onmitochondrial membranethus preventing Bax induced apoptosis [210]

Viruses also encode proteins which act as viral mito-chondrial inhibitors of apoptosis (vMIA) thus protecting thecells A splice variant of UL37 of HCMV acts as vMIA andprotects the cells from apoptosis [211] thereby helping virusesto complete their replication cycle It localizes to mitochon-dria and interacts with ANT [211] and Bax [212 213] HCMVvMIA has an N-terminal mitochondrial localization domainand a C-terminal antiapoptotic domain [211] which recruitsBax tomitochondria and prevents loss ofMMP It protects thecells against CD95 ligation [211] and oxidative stress-inducedcell death [214 215] and prevents mitochondrial fusion [216]thus promoting cell survival

vMIA does not inhibit the apoptotic events upstream ofmitochondria but can influence events like preservation ofATP generation inhibition of Cyto C release and caspase9 activation following induction of apoptosis However theexact mechanisms of the events around vMIA still remain aquestion

6 Viruses Modulate MitochondrialAntiviral Immunity

61 Mitochondrial Antiviral Immunity Cells respond to virusattack by activating a variety of signal transduction pathwaysleading to the production of interferons [217] which limit oreliminate the invading virus The presence of viruses insidethe cell is first sensed by pattern recognition receptors (PRRs)that recognize the pathogen associated molecular patterns(PAMPs) PRRs include toll-like receptors (TLRs) nucleotideoligomerization domain (NOD) like receptors (NLRs) andretinoic acid-inducible gene I (RIG-I) like receptors (RLRs)Mitochondria have been associatedwith RLRs which includeretinoic acid-inducible gene I (RIG-I) [218] and melanomadifferentiation-associated gene 5 (Mda-5) [219] Both arecytoplasm-located RNA helicases that recognize dsRNAThe

N-terminus of RIG-1 has caspase activation and recruitmentdomains (CARDs) whereas C-terminus has RNA helicaseactivity [218] which recognizes and binds to uncapped andunmodified RNA generated by viral polymerases in ATPasedependent manner This causes conformational changes andexposes its CARD domains to bind and activate down-stream effectors leading to the formation of enhanceosome[220] triggering NF120581B production RLRs have recently beenreviewed in detail [221ndash223]

A CARD domain containing protein named mitochon-drial antiviral signaling (MAVS) [15 224] virus-inducedsignaling adaptor (VISA) [225] IFN-120573 promoter stimulator1 (IPS-1) [226] or CARD adaptor inducing IFN-120573 (CARDIF)protein [227] acts downstream of the RIG-I Besides the pres-ence ofN-terminal CARDdomainMAVS contains a proline-rich region and a C-terminal hydrophobic transmembrane(TM) region which targets the protein to the mitochondrialouter membrane and is critical for its activity [15] The TMregion of the MAVS resembles the TM domains of many C-terminal tail-anchored proteins on the outer membrane ofthe mitochondria including Bcl-2 and Bcl-xL [15] Recentreports indicate thatMAVS has an important role in inducingthe antiviral defenses in the cell Overexpression of MAVSleads to the activation of NF120581B and IRF-3 leading to theinduction of type I interferon response which is abrogatedin the absence of MAVS [15] thus indicating the specific roleof MAVS in inducing antiviral response MAVS has also beenshown to prevent apoptosis by its interaction with VDAC[228] and preventing the opening of MPTP

62 Regulation by Viruses Some viruses induce cleavageof MAVs from outer membranes of mitochondria [227229] thus greatly reducing their ability to induce interferonresponse HCV persists in the host by lowering the hostcell immune response including inhibiting the productionof IFN-120573 by RIG-I pathway [230ndash232] The NS34A proteinof HCV colocalizes with mitochondrial MAVS [227 229]leading to the cleavage ofMAVS at amino acid 508 Since freeform of the MAVS is not functional the dislodging of MAVfrom the mitochondria inactivates MAVS [227] thus helpingin paralyzing the host defense against HCV Interestinglyanother member of family Flaviviridae GB virus B shares28 amino acid homology with HCV over the lengths oftheir open-reading frames [233] The NS34A protein ofGB virus also cleaves MAVS in a manner similar to HCVthus effectively compromising the host immune response bypreventing the production of interferons [234] Other viruseslike influenza A translocate RIG-IMAVS components to themitochondria of infected human primary macrophages andregulate the antiviralapoptotic signals increasing the viralsurvivability [235]

7 Viruses Hijack Host Mitochondrial Proteins

Over the years viruses have perfected different strategiesto establish complex relationships with their host with thesole purpose of preserving their existence One such strategyinvolves the hijacking of the host cell mitochondrial proteins


The p32 a mitochondria-associated cellular protein is amember of a complex involved in the import of cytosolicproteins to the nucleus Upon entry into the cell adenovirushijacks this protein and piggybacks it to transport its genometo the nucleus [236] thereby increasing its chances ofsurvival and establishment in the host cell During HIV-1assembly tRNALys iso-acceptors are selectively incorporatedinto virions and tRNALys

3binds to HIV genome and is used

as the primer for reverse transcription [237] In humans asingle gene produces both cytoplasmic and mitochondrialLys tRNA synthetases (LysRSs) by alternative splicing [238]The mitochondrial LysRS is produced as a preprotein whichis transported into the mitochondria The premitochondrialor mitochondrial LysRS is specifically packaged into HIV[239] and acts as a primer to initiate the replication of HIV-I RNA genome which then binds to a site complementaryto the 31015840-end 18 nucleotides of tRNALys

3 It is proposed that

HIV viral protein R (Vpr) alters the permeability of themitochondria [138] leading to the release of premito- ormito-LysRS which then interacts with Vpr [240] and gets packedinto the progeny virions

Viperin an interferon inducible protein is induced in thecells in response to viral infection [241]This protein has beenshown to prevent the release of influenza virus particles fromthe cells by trapping them in lipid rafts inside the cells therebypreventing its dissemination [242] During infection HCMVinduces IFN independent expression of viperin which inter-acts with HCMV encoded vMIA protein resulting in reloca-tion of viperin from ER to mitochondria In mitochondriaviperin interacts with mitochondrial tri-functional proteinand decreasesATP generation by disrupting oxidation of fattyacids which results in disrupting actin cytoskeleton of thecells and enhancing the viral infectivity [243]

8 Viruses Alter IntracellularDistribution of Mitochondria

Viruses alter the intracellular distribution of mitochondriaeither by concentrating the mitochondria near the viralfactories tomeet energy requirements during viral replicationor by cordoning off the mitochondria within cytoplasm toprevent the release of mediators of apoptosis The protein Xof HBV causes microtubule mediated perinuclear clusteringof the mitochondria by p38 mitogen-activated protein kinase(MAPK) mediated dynein activity [244] HCV nonstructuralprotein 4A (NS4A) either alone or together with NS3(in the form of the NS34A polyprotein) accumulates onmitochondria and changes their intracellular distribution[245] HIV-1 infection causes clustering of the mitochon-dria in the infected cells [246] Interestingly ASFV causesthe microtubule-mediated clustering of the mitochondriaaround virus factories in the cell providing energy forvirus release [247] Similar changes were observed in thechick embryo fibroblasts infected with frog virus 3 wheredegenerate mitochondria surrounding virus factories werefound [248]

9 Viruses Mimic the HostMitochondrial Proteins

Molecular mimicry is ldquothe theoretical possibility thatsequence similarities between foreign and self-peptides aresufficient to result in the cross-activation of autoreactive Tor B cells by pathogen-derived peptidesrdquo [249 250] Sincestructure follows the function viruses during their coevo-lution with hosts have evolved to mimic the host proteins tomeet their ends during progression of their life cycle insidethe cell Mimicking aids the viruses to gain access to hostcellular machinery and greatly helps in their survival in thehostile host environment

Mimivirus a member of the newly created virus fam-ily Mimiviridae encodes a eukaryotic mitochondria carrierprotein (VMC-I) [251] which mimics the host cellrsquos mito-chondrial carrier protein and thus controls themitochondrialtransport machinery in infected cells It helps to transportADP dADP TTP dTTP and UTP in exchange for dATPthus exploiting the host for energy requirements duringreplication of its A+T rich genome [251] Besides VMC-I mimivirus encodes several other proteins (L359 L572R776 R596 R740 R824 L81 R151 R900 and L908) withputative mitochondria localization signals which suggestthat mimivirus has evolved a strategy to take over the hostmitochondria and exploited its physiology to compensatefor its energy requirements and biogenesis [251] Viral Bcl-2 homologues (vBcl-2) are other groups of viral proteins thatmimic the host cell Bcl-2s and have been described elsewherein this review

10 Viruses Cause Host MitochondrialDNA Depletion

Mammalian mitochondria contain a small circular genomewhich synthesizes enzymes for oxidative phosphorylationand mitochondrial RNAs (mtRNAs) [27] To increase thechance of survival some viruses appear to have adopted thestrategy of damaging the host cell mitochondrial DNA Sincemitochondria act as a source of energy and play an importantrole in antiviral immunity as well it is possible that damageto mitochondrial DNA may help in evading mitochondrialantiviral immune responses [252]

During productive infection of mammalian cells in vitroHSV-1 induces the rapid and complete degradation of hostmitochondrial DNA [252] The UL125 protein of HSV-1localizes to the mitochondria and induces DNA depletionin the absence of other viral gene products [252 253] Theimmediate early Zta protein of EBV interacts with mito-chondrial single stranded DNA binding protein resultingin reduced mitochondrial DNA (mtDNA) replication andenhanced viral DNA replication [254] HCV causes the reac-tive oxygen species and nitrous oxidemediated DNA damagein host mtDNA [107 255] Interestingly depletion of mtDNAhas also been observed in HIVHCV coinfected humans[256]


11 Conclusions

Though progress has been made in understanding theinteraction of viruses withmitochondria-mediated pathwaysthe pathways linking the detection of viral infection by PRRs(or exact mechanism by which PRRs recognize the PAMPs)and their link to mitochondria-mediated cell death remainpoorly understood Role of the mitochondria in immunityand viral mechanisms to evade them highlights the fact thateven after billions of years of coevolution the fight for thesurvival is still going on Both the host and the viruses areevolving finding new ways to survive It may be interestingto note that mitochondria mediated apoptosis might be anevolutionary adaptation by which they might have effectivelyprevented the entry of other microorganisms trying to gainentry into the host cell and thus effectively establishingthemselves as an integral part of the cell

Acknowledgments

The authors thank Dr Vikram Misra Veterinary Microbiol-ogy University of Saskatchewan for his vision and adviceThey thank Sherry Hueser for carefully proofreading thepaperThe paper is published with the permission of DirectorVIDO as VIDO article no 617 Suresh K Tikoo is fundedby grants from Natural Sciences and Engineering ResearchCouncil of Canada

References

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[2] D C Chan ldquoMitochondria dynamic organelles in diseaseaging and developmentrdquo Cell vol 125 no 7 pp 1241ndash12522006

[3] A Antignani and R J Youle ldquoHow do Bax and Bak leadto permeabilization of the outer mitochondrial membranerdquoCurrent Opinion in Cell Biology vol 18 no 6 pp 685ndash689 2006

[4] H Chen and D C Chan ldquoEmerging functions of mammalianmitochondrial fusion and fissionrdquo Human Molecular Geneticsvol 14 no 2 pp R283ndashR289 2005

[5] I Gradzka ldquoMechanisms and regulation of the programmedcell deathrdquo Postepy Biochemii vol 52 no 2 pp 157ndash165 2006

[6] H M McBride M Neuspiel and S Wasiak ldquoMitochondriamore than just a powerhouserdquo Current Biology vol 16 no 14pp R551ndashR560 2006

[7] G Kroemer L Galluzzi and C Brenner ldquoMitochondrial mem-brane permeabilization in cell deathrdquo Physiological Reviews vol87 no 1 pp 99ndash163 2007

[8] C A Mannella ldquoStructure and dynamics of the mitochondrialinner membrane cristaerdquo Biochimica et Biophysica Acta vol1763 no 5-6 pp 542ndash548 2006

[9] D G Hardie J W Scott D A Pan and E R HudsonldquoManagement of cellular energy by the AMP-activated proteinkinase systemrdquo The FEBS Letters vol 546 no 1 pp 113ndash1202003

[10] R G Jones D R Plas S Kubek et al ldquoAMP-activatedprotein kinase induces a p53-dependent metabolic checkpointrdquoMolecular Cell vol 18 no 3 pp 283ndash293 2005

[11] SMandal P Guptan E Owusu-Ansah andU Banerjee ldquoMito-chondrial regulation of cell cycle progression during devel-opment as revealed by the tenured mutation in DrosophilardquoDevelopmental Cell vol 9 no 6 pp 843ndash854 2005

[12] L E Bakeeva Y S Chentsov and V P Skulachev ldquoMitochon-drial framework (reticulum mitochondriale) in rat diaphragmmusclerdquo Biochimica et Biophysica Acta vol 501 no 3 pp 349ndash369 1978

[13] L E Bakeeva Y S Chentsov and V P Shulachev ldquoIntermito-chondrial contacts inmyocardiocytesrdquo Journal ofMolecular andCellular Cardiology vol 15 no 7 pp 413ndash420 1983

[14] S Honda and S Hirose ldquoStage-specific enhanced expressionof mitochondrial fusion and fission factors during spermato-genesis in rat testisrdquo Biochemical and Biophysical ResearchCommunications vol 311 no 2 pp 424ndash432 2003

[15] R B Seth L Sun C K Ea and Z J Chen ldquoIdentification andcharacterization of MAVS a mitochondrial antiviral signalingprotein that activates NF-120581B and IRF3rdquo Cell vol 122 no 5 pp669ndash682 2005

[16] E Bossy-Wetzel M J Barsoum A Godzik R Schwarzen-bacher and S A Lipton ldquoMitochondrial fission in apoptosisneurodegeneration and agingrdquo Current Opinion in Cell Biologyvol 15 no 6 pp 706ndash716 2003

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[20] RMcFarland RW Taylor andDM Turnbull ldquoMitochondrialdiseasemdashits impact etiology and pathologyrdquo in Current Topicsin Developmental Biology J C St John Ed pp 113ndash155Academic Press New York NY USA 2007

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[22] M Amiry-Moghaddam H Lindland S Zelenin et al ldquoBrainmitochondria contain aquaporin water channels evidence forthe expression of a short AQP9 isoform in the inner mitochon-drial membranerdquo FASEB Journal vol 19 no 11 pp 1459ndash14672005

[23] G Calamita D Ferri P Gena et al ldquoThe inner mitochondrialmembrane has aquaporin-8 water channels and is highlypermeable to waterrdquo The Journal of Biological Chemistry vol280 no 17 pp 17149ndash17153 2005

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[26] E A Shoubridge ldquoThe ABcs of mitochondrial transcriptionrdquoNature Genetics vol 31 no 3 pp 227ndash228 2002

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[31] M van der Laan D P Hutu and P Rehling ldquoOn the mecha-nism of preprotein import by the mitochondrial presequencetranslocaserdquo Biochimica et Biophysica Acta vol 1803 no 6 pp732ndash739 2010

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[34] M J Berridge M D Bootman and P Lipp ldquoCalciummdasha lifeand death signalrdquo Nature vol 395 no 6703 pp 645ndash648 1998

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[36] S V Chorna V I Dosenko N A Strutynsrsquoka H L Vavilovaand V F Sahach ldquoIncreased expression of voltage-dependentanion channel and adenine nucleotide translocase and the sen-sitivity of calcium-induced mitochondrial permeability transi-tion opening pore in the old rat heartrdquo Fiziolohichnyı Zhurnalvol 56 no 4 pp 19ndash25 2010

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[42] A P Halestrap ldquoA pore way to die the role of mitochondriain reperfusion injury and cardioprotectionrdquoBiochemical SocietyTransactions vol 38 no 4 pp 841ndash860 2010

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[48] R S Balaban ldquoThe role of Ca2+ signaling in the coordination ofmitochondrial ATP production with cardiac workrdquo Biochimicaet Biophysica Acta vol 1787 no 11 pp 1334ndash1341 2009

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[52] R A Haworth D R Hunter and H A Berkoff ldquoContracturein isolated adult rat heart cells Role of Ca2+ ATP and compart-mentationrdquo Circulation Research vol 49 no 5 pp 1119ndash11281981

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[54] P Nasr H I Gursahani Z Pang et al ldquoInfluence of cytoso-lic and mitochondrial Ca2+ ATP mitochondrial membranepotential and calpain activity on the mechanism of neurondeath induced by 3-nitropropionic acidrdquo Neurochemistry Inter-national vol 43 no 2 pp 89ndash99 2003

[55] J D Johnston and M D Brand ldquoThe mechanism of Ca2+stimulation of citrulline and N-acetylglutamate synthesis bymitochondriardquo Biochimica et Biophysica Acta vol 1033 no 1pp 85ndash90 1990

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[58] K Lund and B Ziola ldquoCell sonicates used in the analysis of howmeasles and herpes simplex type 1 virus infections influenceVero cell mitochondrial calcium uptakerdquo Canadian Journal ofBiochemistry and Cell Biology vol 63 no 11 pp 1194ndash1197 1985

[59] Y Li D F Boehning T Qian V L Popov and S A WeinmanldquoHepatitis C virus core protein increases mitochondrial ROSproduction by stimulation of Ca2+ uniporter activityrdquo FASEBJournal vol 21 no 10 pp 2474ndash2485 2007

[60] R V Campbell Y Yang T Wang et al ldquoEffects of hepatitis Ccore protein on mitochondrial electron transport and produc-tion of reactive oxygen speciesrdquo Methods in Enzymology vol456 pp 363ndash380 2009


[61] G Gong G Waris R Tanveer and A Siddiqui ldquoHumanhepatitis C virus NS5A protein alters intracellular calciumlevels induces oxidative stress and activates STAT-3 and NF-120581Brdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 17 pp 9599ndash9604 2001

[62] M Kalamvoki and P Mavromara ldquoCalcium-dependent calpainproteases are implicated in processing of the hepatitis C virusNS5A proteinrdquo Journal of Virology vol 78 no 21 pp 11865ndash11878 2004

[63] N Dionisio M V Garcia-Mediavilla S Sanchez-Campos etal ldquoHepatitis C virus NS5A and core proteins induce oxidativestress-mediated calcium signalling alterations in hepatocytesrdquoJournal of Hepatology vol 50 no 5 pp 872ndash882 2009

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[66] S D C Griffin R Harvey D S ClarkeW S Barclay M Harrisand D J Rowlands ldquoA conserved basic loop in hepatitis C virusp7 protein is required for amantadine-sensitive ion channelactivity in mammalian cells but is dispensable for localizationto mitochondriardquo Journal of General Virology vol 85 no 2 pp451ndash461 2004

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[69] M Foti L Cartier V Piguet et al ldquoThe HIV Nef proteinalters Ca2+ signaling in myelomonocytic cells through SH3-mediated protein-protein interactionsrdquoThe Journal of BiologicalChemistry vol 274 no 49 pp 34765ndash34772 1999

[70] A Manninen and K Saksela ldquoHIV-1 Nef interacts with inositoltrisphosphate receptor to activate calcium signaling in T cellsrdquoJournal of Experimental Medicine vol 195 no 8 pp 1023ndash10322002

[71] S Kinoshita L Su M Amano L A Timmerman HKaneshima and G P Nolan ldquoThe T cell activation factor NF-ATc positively regulates HIV-1 replication and gene expressionin T cellsrdquo Immunity vol 6 no 3 pp 235ndash244 1997

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[73] P Tian M K Estes Y Hu J M Ball C Q Zeng and WP Schilling ldquoThe rotavirus nonstructural glycoprotein NSP4mobilizes Ca2+ from the endoplasmic reticulumrdquo Journal ofVirology vol 69 no 9 pp 5763ndash5772 1995

[74] Y Dıaz M E Chemello F Pena et al ldquoExpression of nonstruc-tural rotavirus protein NSP4 mimics Ca2+ homeostasis changesinduced by rotavirus infection in cultured cellsrdquo Journal ofVirology vol 82 no 22 pp 11331ndash11343 2008

[75] J L Zambrano Y Dıaz F Pena et al ldquoSilencing of rotavirusNSP4 or VP7 expression reduces alterations in Ca2+ homeosta-sis induced by infection of cultured cellsrdquo Journal of Virologyvol 82 no 12 pp 5815ndash5824 2008

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Ca2+ sequestered in the endoplasmic reticulum at the end ofvirus cyclerdquo Virus Research vol 130 no 1-2 pp 140ndash150 2007

[77] A Irurzun J Arroyo A Alvarez and L Carrasco ldquoEnhancedintracellular calcium concentration during poliovirus infec-tionrdquo Journal of Virology vol 69 no 8 pp 5142ndash5146 1995

[78] R Aldabe A Irurzun and L Carrasco ldquoPoliovirus protein2BC increases cytosolic free calcium concentrationsrdquo Journal ofVirology vol 71 no 8 pp 6214ndash6217 1997

[79] C Brisac F Teoule A Autret et al ldquoCalcium flux betweenthe endoplasmic reticulum and mitochondrion contributes topoliovirus-induced apoptosisrdquo Journal of Virology vol 84 no23 pp 12226ndash12235 2010

[80] J L Nieva A Agirre S Nir and L Carrasco ldquoMechanisms ofmembrane permeabilization by picornavirus 2B viroporinrdquoTheFEBS Letters vol 552 no 1 pp 68ndash73 2003

[81] F J M van Kuppeveld A S de Jong W J G Melchers andP H G M Willems ldquoEnterovirus protein 2B po(u)res out thecalcium a viral strategy to surviverdquoTrends inMicrobiology vol13 no 2 pp 41ndash44 2005

[82] A S de Jong H J Visch F deMattia et al ldquoThe coxsackievirus2B protein increases efflux of ions from the endoplasmicreticulum and Golgi thereby inhibiting protein traffickingthrough the GolgirdquoThe Journal of Biological Chemistry vol 281no 20 pp 14144ndash14150 2006

[83] A S de Jong F de Mattia M M van Dommelen et al ldquoFunc-tional analysis of picornavirus 2B proteins effects on calciumhomeostasis and intracellular protein traffickingrdquo Journal ofVirology vol 82 no 7 pp 3782ndash3790 2008

[84] F J M van Kuppeveld J G J Hoenderop R L L Smeets etal ldquoCoxsackievirus protein 2Bmodifies endoplasmic reticulummembrane and plasma membrane permeability and facilitatesvirus releaserdquo EMBO Journal vol 16 no 12 pp 3519ndash3532 1997

[85] M Campanella A S de Jong K W H Lanke et al ldquoThe cox-sackievirus 2B protein suppresses apoptotic host cell responsesby manipulating intracellular Ca2+ homeostasisrdquoThe Journal ofBiological Chemistry vol 279 no 18 pp 18440ndash18450 2004

[86] P Bozidis C D Williamson D S Wong and AM Colberg-Poley ldquoTrafficking of UL37 proteins intomitochondrion-associated membranes during permissivehuman cytomegalovirus infectionrdquo Journal of Virology vol 84no 15 pp 7898ndash7903 2010

[87] R Sharon-Friling J Goodhouse A M Colberg-Poley and TShenk ldquoHuman cytomegalovirus pUL37x1 induces the releaseof endoplasmic reticulum calcium storesrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 50 pp 19117ndash19122 2006

[88] P Pinton D Ferrari E Rapizzi F Di Virgilio T Pozzanand R Rizzuto ldquoThe Ca2+ concentration of the endoplasmicreticulum is a key determinant of ceramide-induced apoptosissignificance for the molecular mechanism of Bcl-2 actionrdquoEMBO Journal vol 20 no 11 pp 2690ndash2701 2001

[89] A R Moise J R Grant T Z Vitalis and W A Jefferies ldquoAde-novirus E3-67K maintains calcium homeostasis and preventsapoptosis and arachidonic acid releaserdquo Journal of Virology vol76 no 4 pp 1578ndash1587 2002

[90] P H Chan K Niizuma and H Endo ldquoOxidative stressand mitochondrial dysfunction as determinants of ischemicneuronal death and survivalrdquo Journal of Neurochemistry vol109 no 1 pp 133ndash138 2009

[91] F Muller A R Crofts and D M Kramer ldquoMultiple Q-cyclebypass reactions at the Qo site of the cytochrome bc1 complexrdquoBiochemistry vol 41 no 25 pp 7866ndash7874 2002


[92] F L Muller A G Roberts M K Bowman and D M KramerldquoArchitecture of the Q-o site of the cytochrome bc1 complexprobed by superoxide productionrdquo Biochemistry vol 42 no 21pp 6493ndash6499 2003

[93] F L Muller Y Liu and H van Remmen ldquoComplex III releasessuperoxide to both sides of the innermitochondrialmembranerdquoThe Journal of Biological Chemistry vol 279 no 47 pp 49064ndash49073 2004

[94] V P Skulachev ldquoBioenergetic aspects of apoptosis necrosis andmitoptosisrdquo Apoptosis vol 11 no 4 pp 473ndash485 2006

[95] J St-Pierre J A Buckingham S J Roebuck and M D BrandldquoTopology of superoxide production from different sites inthe mitochondrial electron transport chainrdquo The Journal ofBiological Chemistry vol 277 no 47 pp 44784ndash44790 2002

[96] D Han F Antunes R Canali D Rettori and E CadenasldquoVoltage-dependent anion channels control the release of thesuperoxide anion frommitochondria to cytosolrdquoThe Journal ofBiological Chemistry vol 278 no 8 pp 5557ndash5563 2003

[97] SMiwa J St-Pierre L Partridge andMD Brand ldquoSuperoxideand hydrogen peroxide production by Drosophila mitochon-driardquo Free Radical Biology and Medicine vol 35 no 8 pp 938ndash948 2003

[98] H Tsutsui T Ide and S Kinugawa ldquoMitochondrial oxidativestress DNA damage and heart failurerdquoAntioxidants and RedoxSignaling vol 8 no 9-10 pp 1737ndash1744 2006

[99] D F Stowe and A K S Camara ldquoMitochondrial reactiveoxygen species production in excitable cells modulators ofmitochondrial and cell functionrdquo Antioxidants and Redox Sig-naling vol 11 no 6 pp 1373ndash1414 2009

[100] H Tsutsui S Kinugawa and S Matsushima ldquoMitochondrialoxidative stress and dysfunction in myocardial remodellingrdquoCardiovascular Research vol 81 no 3 pp 449ndash456 2009

[101] JM Taylor D Quilty L Banadyga andM Barry ldquoThe vacciniavirus protein F1L interacts with Bim and inhibits activationof the pro-apoptotic protein Baxrdquo The Journal of BiologicalChemistry vol 281 no 51 pp 39728ndash39739 2006

[102] M Ott J D Robertson V Gogvadze B Zhivotovsky and SOrrenius ldquoCytochrome c release from mitochondria proceedsby a two-step processrdquo Proceedings of the National Academy ofSciences of the United States of America vol 99 no 3 pp 1259ndash1263 2002

[103] S Raha A TMyint L Johnstone and BH Robinson ldquoControlof oxygen free radical formation frommitochondrial complex Iroles for protein kinase A and pyruvate dehydrogenase kinaserdquoFree Radical Biology and Medicine vol 32 no 5 pp 421ndash4302002

[104] K A McGuire A U Barlan T M Griffin and C M WiethoffldquoAdenovirus type 5 rupture of lysosomes leads to cathepsinB-dependent mitochondrial stress and production of reactiveoxygen speciesrdquo Journal of Virology vol 85 no 20 pp 10806ndash10813 2011

[105] S Nishina K Hino M Korenaga et al ldquoHepatitis C virus-induced reactive oxygen species raise hepatic iron level in miceby reducing hepcidin transcriptionrdquo Gastroenterology vol 134no 1 pp 226ndash238 2008

[106] N S R de Mochel S Seronello S H Wang et al ldquoHepatocyteNAD(P)H oxidases as an endogenous source of reactive oxygenspecies during hepatitis C virus infectionrdquo Hepatology vol 52no 1 pp 47ndash59 2010

[107] M J Hsieh Y S Hsieh T Y Chen and H L Chiou ldquoHepatitisC virus E2 protein induce reactive oxygen species (ROS)-related

fibrogenesis in the HSC-T6 hepatic stellate cell linerdquo Journal ofCellular Biochemistry vol 112 no 1 pp 233ndash243 2010

[108] K Machida G Mcnamara K T Cheng et al ldquoHepatitisC virus inhibits DNA damage repair through reactive oxy-gen and nitrogen species and by interfering with the ATM-NBS1Mre11Rad50 DNA repair pathway in monocytes andhepatocytesrdquo Journal of Immunology vol 185 no 11 pp 6985ndash6998 2010

[109] I I Kruman A Nath and M P Mattson ldquoHIV-1 protein tatinduces apoptosis of hippocampal neurons by a mechanisminvolving caspase activation calcium overload and oxidativestressrdquo Experimental Neurology vol 154 no 2 pp 276ndash2881998

[110] M A Baugh ldquoHIV reactive oxygen species enveloped virusesand hyperbaric oxygenrdquo Medical Hypotheses vol 55 no 3 pp232ndash238 2000

[111] L Gil A Tarinas D Hernandez et al ldquoAltered oxidativestress indexes related to disease progression marker in humanimmunodeficiency virus infected patients with antiretroviraltherapyrdquo Biomedicine and Aging Pathology vol 1 no 1 pp 8ndash15 2011

[112] C W Pyo Y L Yang N K Yoo and S Y Choi ldquoReactiveoxygen species activate HIV long terminal repeat via post-translational control of NF-120581Brdquo Biochemical and BiophysicalResearch Communications vol 376 no 1 pp 180ndash185 2008

[113] W LinGWu S Li et al ldquoHIVandHCVcooperatively promotehepatic fibrogenesis via induction of reactive oxygen speciesand NF 120581Brdquo The Journal of Biological Chemistry vol 286 no4 pp 2665ndash2674 2011

[114] S Lassoued B Gargouri A E F El Feki H Attia and Jvan Pelt ldquoTranscription of the epstein-barr virus lytic cycleactivator BZLF-1 during oxidative stress inductionrdquo BiologicalTrace Element Research vol 137 no 1 pp 13ndash22 2010

[115] S Lassoued R B Ameur W Ayadi B Gargouri R BMansour andH Attia ldquoEpstein-Barr virus induces an oxidativestress during the early stages of infection in B lymphocytesepithelial and lymphoblastoid cell linesrdquoMolecular andCellularBiochemistry vol 313 no 1-2 pp 179ndash186 2008

[116] B Gargouri J van Pelt A E F El Feki H Attia and SLassoued ldquoInduction of Epstein-Barr virus (EBV) lytic cyclein vitro causes oxidative stress in lymphoblastoid B cell linesrdquoMolecular and Cellular Biochemistry vol 324 no 1-2 pp 55ndash632009

[117] Y J Kim J K Jung S Y Lee and K L Jang ldquoHepatitis B virusX protein overcomes stress-induced premature senescence byrepressing p16INK4a expression via DNAmethylationrdquo CancerLetters vol 288 no 2 pp 226ndash235 2010

[118] L Hu L Chen G Yang et al ldquoHBx sensitizes cells to oxidativestress-induced apoptosis by accelerating the loss of Mcl-1protein via caspase-3 cascaderdquoMolecular Cancer vol 10 article43 2011

[119] S Schaedler J Krause K Himmelsbach et al ldquoHepatitis B virusinduces expression of antioxidant response element-regulatedgenes by activation of Nrf2rdquoThe Journal of Biological Chemistryvol 285 no 52 pp 41074ndash41086 2010

[120] R Srisuttee S S Koh E H Park et al ldquoUp-regulation ofFoxo4mediated by hepatitis B virus X protein confers resistanceto oxidative stress-induced cell deathrdquo International Journal ofMolecular Medicine vol 28 no 2 pp 255ndash260 2011

[121] A Bhargava S Khan H Panwar et al ldquoOccult hepatitis B virusinfection with low viremia induces DNA damage apoptosis


and oxidative stress in peripheral blood lymphocytesrdquo VirusResearch vol 153 no 1 pp 143ndash150 2010

[122] Y Ano A Sakudo T Kimata R Uraki K Sugiura and TOnodera ldquoOxidative damage to neurons caused by the induc-tion of microglial NADPH oxidase in encephalomyocarditisvirus infectionrdquo Neuroscience Letters vol 469 no 1 pp 39ndash432010

[123] M Colombini E Blachly-Dyson and M Forte ldquoVDAC achannel in the outer mitochondrial membranerdquo Ion channelsvol 4 pp 169ndash202 1996

[124] M Forte E Blachly-Dyson and M Colombini ldquoStructure andfunction of the yeast outer mitochondrial membrane channelVDACrdquo Society of General Physiologists Series vol 51 pp 145ndash154 1996

[125] S Villinger R Briones K Giller et al ldquoFunctional dynamicsin the voltage-dependent anion channelrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 107 no 52 pp 22546ndash22551 2010

[126] E Pebay-Peyroula C Dahout-Gonzalez R Kahn V TrezeguetG J Lauquin and G Brandolin ldquoStructure of mitochon-drial ADPATP carrier in complex with carboxyatractylosiderdquoNature vol 426 no 6962 pp 39ndash44 2003

[127] D R Hunter and R A Haworth ldquoThe Ca2+-induced mem-brane transition in mitochondria The protective mechanismsrdquoArchives of Biochemistry and Biophysics vol 195 no 2 pp 453ndash459 1979

[128] K D Garlid X Sun P Paucek and G Woldegiorgis ldquoMito-chondrial cation transport systemsrdquo Methods in Enzymologyvol 260 pp 331ndash348 1995

[129] P Bernardi ldquoMitochondrial transport of cations channelsexchangers and permeability transitionrdquo Physiological Reviewsvol 79 no 4 pp 1127ndash1155 1999

[130] A PHalestrap ldquoCalciummitochondria and reperfusion injurya pore way to dierdquo Biochemical Society Transactions vol 34 no2 pp 232ndash237 2006

[131] K Szydlowska and M Tymianski ldquoCalcium ischemia andexcitotoxicityrdquo Cell Calcium vol 47 no 2 pp 122ndash129 2010

[132] C Piccoli R Scrima G Quarato et al ldquoHepatitis C virus pro-tein expression causes calcium-mediated mitochondrial bioen-ergetic dysfunction and nitro-oxidative stressrdquoHepatology vol46 no 1 pp 58ndash65 2007

[133] M Gac J Bigda and T W Vahlenkamp ldquoIncreased mitochon-drial superoxide dismutase expression and lowered productionof reactive oxygen species during rotavirus infectionrdquo Virologyvol 404 no 2 pp 293ndash303 2010

[134] S Carrere-Kremer C Montpellier-Pala L Cocquerel CWychowski F Penin and J Dubuisson ldquoSubcellular localiza-tion and topology of the p7 polypeptide of hepatitis C virusrdquoJournal of Virology vol 76 no 8 pp 3720ndash3730 2002

[135] M E Gonzalez and L Carrasco ldquoViroporinsrdquoTheFEBS Lettersvol 552 no 1 pp 28ndash34 2003

[136] D Pavlovic D C A Neville O Argaud et al ldquoThe hepatitis Cvirus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivativesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 100 no10 pp 6104ndash6108 2003

[137] A Azuma A Matsuo T Suzuki T Kurosawa X Zhang andY Aida ldquoHuman immunodeficiency virus type 1 Vpr inducescell cycle arrest at the G1 phase and apoptosis via disruption ofmitochondrial function in rodent cellsrdquoMicrobes and Infectionvol 8 no 3 pp 670ndash679 2006

[138] E Jacotot L Ravagnan M Loeffler et al ldquoThe HIV-1 viral pro-tein R induces apoptosis via a direct effect on themitochondrialpermeability transition porerdquo Journal of ExperimentalMedicinevol 191 no 1 pp 33ndash46 2000

[139] A Deniaud C Brenner and G Kroemer ldquoMitochondrialmembrane permeabilization byHIV-1 VprrdquoMitochondrion vol4 no 2-3 pp 223ndash233 2004

[140] A Macho M A Calzado L Jimenez-Reina E Ceballos JLeon and E Munoz ldquoSusceptibility of HIV-1-TAT transfectedcells to undergo apoptosis Biochemical mechanismsrdquo Onco-gene vol 18 no 52 pp 7543ndash7551 1999

[141] H Everett M Barry X Sun et al ldquoThe myxoma poxvirusprotein M11L prevents apoptosis by direct interaction withthe mitochondrial permeability transition porerdquo Journal ofExperimental Medicine vol 196 no 9 pp 1127ndash1139 2002

[142] H Everett M Barry S F Lee et al ldquoM11L a novelmitochondria-localized protein of myxoma virus that blocksapoptosis of infected leukocytesrdquo Journal of ExperimentalMedicine vol 191 no 9 pp 1487ndash1498 2000

[143] J L Macen K A Graham S F Lee M Schreiber L KBoshkov and G McFadden ldquoExpression of the myxoma virustumor necrosis factor receptor homologue and M11L genes isrequired to prevent virus-induced apoptosis in infected rabbitT lymphocytesrdquo Virology vol 218 no 1 pp 232ndash237 1996

[144] S T Wasilenko T L Stewart A F A Meyers and MBarry ldquoVaccinia virus encodes a previously uncharacterizedmitochondrial-associated inhibitor of apoptosisrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 100 no 2 pp 14345ndash14350 2003

[145] S T Wasilenko L Banadyga D Bond and M Barry ldquoThevaccinia virus F1L protein interacts with the proapoptoticprotein Bak and inhibits Bak activationrdquo Journal of Virology vol79 no 22 pp 14031ndash14043 2005

[146] S T Wasilenko A F A Meyers K V Helm and M BarryldquoVaccinia virus infection disarms the mitochondrion-mediatedpathway of the apoptotic cascade bymodulating the permeabil-ity transition porerdquo Journal of Virology vol 75 no 23 pp 11437ndash11448 2001

[147] K Bruns N Studtrucker A Sharma et al ldquoStructural char-acterization and oligomerization of PB1-F2 a proapoptoticinfluenza A virus proteinrdquo The Journal of Biological Chemistryvol 282 no 1 pp 353ndash363 2007

[148] W Chen P A Calvo DMalide et al ldquoA novel influenza A virusmitochondrial protein that induces cell deathrdquoNatureMedicinevol 7 no 12 pp 1306ndash1312 2001

[149] J S Gibbs D Malide F Hornung J R Bennink and J WYewdell ldquoThe influenza A virus PB1-F2 protein targets the innermitochondrial membrane via a predicted basic amphipathichelix that disrupts mitochondrial functionrdquo Journal of Virologyvol 77 no 13 pp 7214ndash7224 2003

[150] M Henkel D Mitzner P Henklein et al ldquoProapoptoticinfluenza A virus protein PB1-F2 forms a nonselective ionchannelrdquo PLoS ONE vol 5 no 6 Article ID e11112 2010

[151] M Danishuddin S N Khan and A U Khan ldquoMolecularinteractions between mitochondrial membrane proteins andtheC-terminal domain of PB1-F2 an in silico approachrdquo Journalof Molecular Modeling vol 16 no 3 pp 535ndash541 2010

[152] M Silic-Benussi O Marin R Biasiotto D M DrsquoAgostinoand V Ciminale ldquoEffects of human T-cell leukemia virus type1 (HTLV-1) p13 on mitochondrial K+ permeability a newmember of the viroporin familyrdquo The FEBS Letters vol 584no 10 pp 2070ndash2075 2010


[153] V Ciminale L Zotti D M DrsquoAgostino et al ldquoMitochondrialtargeting of the p13(II) protein coded by the x-II ORF ofhuman T-cell leukemialymphotropic virus type I (HTLV-I)rdquoOncogene vol 18 no 31 pp 4505ndash4514 1999

[154] R Biasiotto P Aguiari R Rizzuto P Pinton D M DrsquoAgostinoand V Ciminale ldquoThe p13 protein of human T cell leukemiavirus type 1 (HTLV-1) modulates mitochondrial membranepotential and calcium uptakerdquo Biochimica et Biophysica Actavol 1797 no 6-7 pp 945ndash951 2010

[155] M Silic-Benussi I Cavallari T Zorzan et al ldquoSuppression oftumor growth and cell proliferation by p13II a mitochondrialprotein of human T cell leukemia virus type 1rdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 17 pp 6629ndash6634 2004

[156] W A Nudson J Rovnak M Buechner and S L QuackenbushldquoWalleye dermal sarcoma virus Orf C is targeted to the mito-chondriardquo Journal of General Virology vol 84 no 2 pp 375ndash381 2003

[157] E White ldquoMechanisms of apoptosis regulation by viral onco-genes in infection and tumorigenesisrdquo Cell Death and Differen-tiation vol 13 no 8 pp 1371ndash1377 2006

[158] L Galluzzi C Brenner E Morselli Z Touat and G KroemerldquoViral control of mitochondrial apoptosisrdquo PLoS Pathogens vol4 no 5 Article ID e1000018 2008

[159] C A Benedict P S Norris and C F Ware ldquoTo kill or be killedviral evasion of apoptosisrdquoNature Immunology vol 3 no 11 pp1013ndash1018 2002

[160] S Hay and G Kannourakis ldquoA time to kill viral manipulationof the cell death programrdquo Journal of General Virology vol 83no 7 pp 1547ndash1564 2002

[161] J F Kerr A H Wyllie and A R Currie ldquoApoptosis abasic biological phenomenon with wide-ranging implicationsin tissue kineticsrdquo The British Journal of Cancer vol 26 no 4pp 239ndash257 1972

[162] E Gulbins S Dreschers and J Bock ldquoRole of mitochondria inapoptosisrdquo Experimental Physiology vol 88 no 1 pp 85ndash902003

[163] V Borutaite ldquoMitochondria as decision-makers in cell deathrdquoEnvironmental and Molecular Mutagenesis vol 51 no 5 pp406ndash416 2010

[164] C M Sanfilippo and J A Blaho ldquoThe facts of deathrdquo Inter-national Reviews of Immunology vol 22 no 5-6 pp 327ndash3402003

[165] X Liu C N Kim J Yang R Jemmerson and XWang ldquoInduc-tion of apoptotic program in cell-free extracts requirement fordATP and cytochrome crdquo Cell vol 86 no 1 pp 147ndash157 1996

[166] C Castanier and D Arnoult ldquoMitochondrial dynamics duringapoptosisrdquoMedecineSciences vol 26 no 10 pp 830ndash835 2010

[167] H Zou W J Henzel X Liu A Lutschg and X Wang ldquoApaf-1a human protein homologous to C elegans CED-4 participatesin cytochrome c-dependent activation of caspase-3rdquo Cell vol90 no 3 pp 405ndash413 1997

[168] M Karbowski ldquoMitochondria on guard role of mitochondrialfusion and fission in the regulation of apoptosisrdquo Advances inExperimental Medicine and Biology vol 687 pp 131ndash142 2010

[169] X M Sun M MacFarlane J Zhuang B B Wolf D R Greenand G M Cohen ldquoDistinct caspase cascades are initiatedin receptor-mediated and chemical-induced apoptosisrdquo TheJournal of Biological Chemistry vol 274 no 8 pp 5053ndash50601999

[170] A Ashkenazi and V M Dixit ldquoDeath receptors signaling andmodulationrdquo Science vol 281 no 5381 pp 1305ndash1308 1998

[171] K F Ferri and G Kroemer ldquoOrganelle-specific initiation of celldeath pathwaysrdquo Nature Cell Biology vol 3 no 11 pp E255ndashE263 2001

[172] L Ravagnan T Roumier and G Kroemer ldquoMitochondriathe killer organelles and their weaponsrdquo Journal of CellularPhysiology vol 192 no 2 pp 131ndash137 2002

[173] S Ohta ldquoA multi-functional organelle mitochondrion isinvolved in cell death proliferation and diseaserdquo CurrentMedicinal Chemistry vol 10 no 23 pp 2485ndash2494 2003

[174] N N Danial A Gimenez-Cassina and D Tondera ldquoHomeo-static functions of BCL-2 proteins beyond apoptosisrdquo Advancesin Experimental Medicine and Biology vol 687 pp 1ndash32 2010

[175] M E Soriano and L Scorrano ldquoThe interplay between BCL-2 family proteins and mitochondrial morphology in the reg-ulation of apoptosisrdquo Advances in Experimental Medicine andBiology vol 687 pp 97ndash114 2010

[176] S Krishna I C C Low and S Pervaiz ldquoRegulation ofmitochondrial metabolism yet another facet in the biology ofthe oncoprotein Bcl-2rdquo Biochemical Journal vol 435 no 3 pp545ndash551 2011

[177] F Llambi and D R Green ldquoApoptosis and oncogenesis giveand take in the BCL-2 familyrdquo Current Opinion in Genetics andDevelopment vol 21 no 1 pp 12ndash20 2011

[178] L Scorrano and S J Korsmeyer ldquoMechanisms of cytochromec release by proapoptotic BCL-2 family membersrdquo Biochemicaland Biophysical Research Communications vol 304 no 3 pp437ndash444 2003

[179] M Crompton ldquoBax Bid and the permeabilization of themitochondrial outer membrane in apoptosisrdquo Current Opinionin Cell Biology vol 12 no 4 pp 414ndash419 2000

[180] N J Waterhouse J E Ricci and D R Green ldquoAnd all of a sud-den itrsquos over mitochondrial outer-membrane permeabilizationin apoptosisrdquo Biochimie vol 84 no 2-3 pp 113ndash121 2002

[181] A S Belzacq H L A Vieira F Verrier et al ldquoBcl-2 andBax modulate adenine nucleotide translocase activityrdquo CancerResearch vol 63 no 2 pp 541ndash546 2003

[182] N Zamzami and G Kroemer ldquoApoptosis mitochondrial mem-brane permeabilizationmdashthe (w)hole storyrdquo Current Biologyvol 13 no 2 pp R71ndashR73 2003

[183] G Paradies G Petrosillo V Paradies and F M RuggieroldquoRole of cardiolipin peroxidation and Ca2+ in mitochondrialdysfunction and diseaserdquo Cell Calcium vol 45 no 6 pp 643ndash650 2009

[184] A Cuconati and E White ldquoViral homologs of BCL-2 roleof apoptosis in the regulation of virus infectionrdquo Genes andDevelopment vol 16 no 19 pp 2465ndash2478 2002

[185] B J Thomson ldquoViruses and apoptosisrdquo International Journal ofExperimental Pathology vol 82 no 2 pp 65ndash76 2001

[186] D Perez and EWhite ldquoTNF-120572 signals apoptosis through a bid-dependent conformational change in Bax that is inhibited byE1B 19KrdquoMolecular Cell vol 6 no 1 pp 53ndash63 2000

[187] B M Putzer T Stiewe K Parssanedjad S Rega and H EscheldquoE1A is sufficient by itself to induce apoptosis independentof p53 and other adenoviral gene productsrdquo Cell Death andDifferentiation vol 7 no 2 pp 177ndash188 2000

[188] L Banadyga J Gerig T Stewart and M Barry ldquoFowlpox virusencodes a Bcl-2 homologue that protects cells from apoptoticdeath through interaction with the proapoptotic protein bakrdquoJournal of Virology vol 81 no 20 pp 11032ndash11045 2007


[189] A Brun C Rivas M Esteban J M Escribano and C AlonsoldquoAfrican swine fever virus gene A179L a viral homologue of bcl-2 protects cells fromprogrammed cell deathrdquoVirology vol 225no 1 pp 227ndash230 1996

[190] Y Revilla A Cebrian E Baixeras C Martınez E Vinuela andM L Salas ldquoInhibition of apoptosis by the African swine fevervirus Bcl-2 homologue role of the BH1 domainrdquo Virology vol228 no 2 pp 400ndash404 1997

[191] T Derfuss H Fickenscher M S Kraft et al ldquoAntiapoptoticactivity of the herpesvirus saimiri-encoded Bcl-2 homologstabilization of mitochondria and inhibition of caspase-3-likeactivityrdquo Journal of Virology vol 72 no 7 pp 5897ndash5904 1998

[192] W L Marshall C Yim E Gustafson et al ldquoEpstein-Barr virusencodes a novel homolog of the bcl-2 oncogene that inhibitsapoptosis and associates with Bax and Bakrdquo Journal of Virologyvol 73 no 6 pp 5181ndash5185 1999

[193] X M Yin Z N Oltvai and S J Korsmeyer ldquoBH1 and BH2domains of Bcl-2 are required for inhibition of apoptosis andheterodimerization with Baxrdquo Nature vol 369 no 6478 pp321ndash323 1994

[194] Z Rahmani K W Huh R Lasher and A Siddiqui ldquoHepatitisB virus X protein colocalizes to mitochondria with a humanvoltage-dependent anion channel HVDAC3 and alters itstransmembrane potentialrdquo Journal of Virology vol 74 no 6 pp2840ndash2846 2000

[195] Y W Lu and W N Chen ldquoHuman hepatitis B virus Xprotein induces apoptosis in HepG2 cells role of BH3 domainrdquoBiochemical and Biophysical Research Communications vol 338no 3 pp 1551ndash1556 2005

[196] Y Tanaka F Kanai T Kawakami et al ldquoInteraction of thehepatitis B virus X protein (HBx) with heat shock protein 60enhances HBx-mediated apoptosisrdquo Biochemical and Biophysi-cal Research Communications vol 318 no 2 pp 461ndash469 2004

[197] J Diao A A Khine F Sarangi et al ldquoX protein of hepatitis Bvirus inhibits Fas-mediated apoptosis and is associated with up-regulation of the SAPKJNK pathwayrdquoThe Journal of BiologicalChemistry vol 276 no 11 pp 8328ndash8340 2001

[198] A S Kekule U Lauer L Weiss B Luber and P H Hof-schneider ldquoHepatitis B virus transactivator HBx uses a tumourpromoter signalling pathwayrdquo Nature vol 361 no 6414 pp742ndash745 1993

[199] F Su and R J Schneider ldquoHepatitis B virus HBx proteinactivates transcription factor NF-120581B by acting onmultiple cyto-plasmic inhibitors of rel-related proteinsrdquo Journal of Virologyvol 70 no 7 pp 4558ndash4566 1996

[200] J Benn F Su M Doria and R J Schneider ldquoHepatitis B virusHBx protein induces transcription factor AP-1 by activation ofextracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinasesrdquo Journal of Virology vol 70 no 8 pp4978ndash4985 1996

[201] F Henkler A R Lopes M Jones and R Koshy ldquoErk-independent partial activation of AP-1 sites by the hepatitis Bvirus HBx proteinrdquo Journal of General Virology vol 79 no 11pp 2737ndash2742 1998

[202] W L Shih M L Kuo S E Chuang A L Cheng and SL Doong ldquoHepatitis b virus x protein inhibits transforminggrowth factor-120573-induced apoptosis through the activation ofphosphatidylinositol 3-kinase pathwayrdquo The Journal of Biolog-ical Chemistry vol 275 no 33 pp 25858ndash25864 2000

[203] J KomanoM Sugiura and K Takada ldquoEpstein-barr virus con-tributes to the malignant phenotype and to apoptosis resistance

in Burkittrsquos lymphoma cell line Akatardquo Journal of Virology vol72 no 11 pp 9150ndash9156 1998

[204] D S BellowsMHowell C Pearson S A Hazlewood and JMHardwick ldquoEpstein-Barr virus BALF1 is a BCL-2-like antagonistof the herpesvirus antiapoptotic BCL-2 proteinsrdquo Journal ofVirology vol 76 no 5 pp 2469ndash2479 2002

[205] A M Flanagan and A Letai ldquoBH3 domains define selectiveinhibitory interactions with BHRF-1 and KSHV BCL-2rdquo CellDeath and Differentiation vol 15 no 3 pp 580ndash588 2008

[206] M Thomas and L Banks ldquoHuman papillomavirus (HPV) E6interactions with Bak are conserved amongst E6 proteins fromhigh and low risk HPV typesrdquo Journal of General Virology vol80 no 6 pp 1513ndash1517 1999

[207] S Jackson C Harwood M Thomas L Banks and A StoreyldquoRole of Bak in UV-induced apoptosis in skin cancer andabrogation by HPV E6 proteinsrdquo Genes and Development vol14 no 23 pp 3065ndash3073 2000

[208] S Leverrier D Bergamaschi L Ghali et al ldquoRole of HPV E6proteins in preventing UVB-induced release of pro-apoptoticfactors from the mitochondriardquo Apoptosis vol 12 no 3 pp549ndash560 2007

[209] Z M Sun Y Xiao L L Ren X B Lei and J W WangldquoEnterovirus 71 induces apoptosis in a Bax dependent mannerrdquoZhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi vol 25no 1 pp 49ndash52 2011

[210] C S Ilkow I S Goping and T C Hobman ldquoThe rubella viruscapsid is an anti-apoptotic protein that attenuates the pore-forming ability of Baxrdquo PLoS Pathogens vol 7 no 2 Article IDe1001291 2011

[211] V S Goldmacher L M Bartle A Skaletskaya et al ldquoAcytomegalovirus-encoded mitochondria-localized inhibitor ofapoptosis structurally unrelated to Bcl-2rdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 22 pp 12536ndash12541 1999

[212] D Arnoult LM Bartle A Skaletskaya et al ldquoCytomegaloviruscell death suppressor vMIA blocks Bax- but not Bak-mediatedapoptosis by binding and sequestering Bax at mitochondriardquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 101 no 21 pp 7988ndash7993 2004

[213] D Poncet N Larochette A Pauleau et al ldquoAn anti-apoptoticviral protein that recruits Bax to mitochondriardquo The Journal ofBiological Chemistry vol 279 no 21 pp 22605ndash22614 2004

[214] H L A Vieira A S Belzacq D Haouzi et al ldquoThe adeninenucleotide translocator a target of nitric oxide peroxynitriteand 4-hydroxynonenalrdquo Oncogene vol 20 no 32 pp 4305ndash4316 2001

[215] P BoyaM CMorales R Gonzalez-Polo et al ldquoThe chemopre-ventive agent N-(4-hydroxyphenyl)retinamide induces apopto-sis through amitochondrial pathway regulated by proteins fromthe Bcl-2 familyrdquoOncogene vol 22 no 40 pp 6220ndash6230 2003

[216] A L McCormick V L Smith D Chow and E S MocarskildquoDisruption of mitochondrial networks by the humancytomegalovirus UL37 gene product viral mitochondrion-localized inhibitor of apoptosisrdquo Journal of Virology vol 77 no1 pp 631ndash641 2003

[217] M G Katze Y He and M Gale Jr ldquoViruses and interferon afight for supremacyrdquo Nature Reviews Immunology vol 2 no 9pp 675ndash687 2002

[218] M Yoneyama M Kikuchi T Natsukawa et al ldquoThe RNAhelicase RIG-I has an essential function in double-strandedRNA-induced innate antiviral responsesrdquo Nature Immunologyvol 5 no 7 pp 730ndash737 2004


[219] J Andrejeva K S Childs D F Young et al ldquoThe V proteins ofparamyxoviruses bind the IFN-inducible RNA helicase mda-5and inhibit its activation of the IFN-120573 promoterrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 49 pp 17264ndash17269 2004

[220] T Maniatis J V Falvo T H Kim et al ldquoStructure and functionof the interferon-120573 enhanceosomerdquo Cold Spring Harbor Sym-posia on Quantitative Biology vol 63 pp 609ndash620 1998

[221] I Scott ldquoThe role of mitochondria in the mammalian antiviraldefense systemrdquoMitochondrion vol 10 no 4 pp 316ndash320 2010

[222] C Castanier and D Arnoult ldquoMitochondrial localization ofviral proteins as a means to subvert host defenserdquo Biochimicaet Biophysica Acta vol 1813 no 4 pp 575ndash583 2011

[223] C Wang X Liu and B Wei ldquoMitochondrion an emergingplatform critical for host antiviral signalingrdquo Expert Opinion onTherapeutic Targets vol 15 no 5 pp 647ndash665 2011

[224] R B Seth L Sun and Z J Chen ldquoAntiviral innate immunitypathwaysrdquo Cell Research vol 16 no 2 pp 141ndash147 2006

[225] L G Xu Y Y Wang K J Han L Y Li Z Zhai and H B ShuldquoVISA is an adapter protein required for virus-triggered IFN-120573signalingrdquoMolecular Cell vol 19 no 6 pp 727ndash740 2005

[226] T Kawai K Takahashi S Sato et al ldquoIPS-1 an adaptor trig-gering RIG-I- andMda5-mediated type I interferon inductionrdquoNature Immunology vol 6 no 10 pp 981ndash988 2005

[227] E Meylan J Curran K Hofmann et al ldquoCardif is an adaptorprotein in the RIG-I antiviral pathway and is targeted byhepatitis C virusrdquoNature vol 437 no 7062 pp 1167ndash1172 2005

[228] Y Xu H Zhong and W Shi ldquoMAVS protects cells fromapoptosis by negatively regulating VDAC1rdquo Molecular andCellular Biochemistry vol 375 no 1-2 p 219 2010

[229] X D Li L Sun R B Seth G Pineda and Z J ChenldquoHepatitis C virus protease NS34A cleaves mitochondrialantiviral signaling protein off the mitochondria to evade innateimmunityrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 102 no 49 pp 17717ndash177222005

[230] E Foy K Li CWang et al ldquoRegulation of interferon regulatoryfactor-3 by the hepatitis C virus serine proteaserdquo Science vol300 no 5622 pp 1145ndash1148 2003

[231] A Breiman N Grandvaux R Lin et al ldquoInhibition of RIG-I-dependent signaling to the interferon pathway during hepatitisC virus expression and restoration of signaling by IKK120576rdquo Journalof Virology vol 79 no 7 pp 3969ndash3978 2005

[232] E Foy K Li R Sumpter Jr et al ldquoControl of antiviral defensesthrough hepatitis C virus disruption of retinoic acid-induciblegene-I signalingrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 8 pp 2986ndash2991 2005

[233] B Beames D Chavez and R E Lanford ldquoGB virus B as amodelfor hepatitis C virusrdquo ILAR Journal vol 42 no 2 pp 152ndash1602001

[234] Z Chen Y Benureau R Rijnbrand et al ldquoGB virus B disruptsRIG-I signaling by NS34A-mediated cleavage of the adaptorprotein MAVSrdquo Journal of Virology vol 81 no 2 pp 964ndash9762007

[235] T Ohman J Rintahaka N Kalkkinen S Matikainen andT A Nyman ldquoActin and RIG-IMAVS signaling componentstranslocate to mitochondria upon influenza a virus infection ofhuman primary macrophagesrdquo Journal of Immunology vol 182no 9 pp 5682ndash5692 2009

[236] D A Matthews and W C Russell ldquoAdenovirus core protein Vinteracts with p32mdasha protein which is associated with both themitochondria and the nucleusrdquo Journal of General Virology vol79 no 7 pp 1677ndash1685 1998

[237] S Cen A Khorchid H Javanbakht et al ldquoIncorporation oflysyl-tRNA synthetase into human immunodeficiency virustype 1rdquo Journal of Virology vol 75 no 11 pp 5043ndash5048 2001

[238] E Tolkunova H Park J Xia M P King and E DavidsonldquoThehuman lysyl-tRNA synthetase gene encodes both the cyto-plasmic and mitochondrial enzymes by means of an unusualalternative splicing of the primary transcriptrdquo The Journal ofBiological Chemistry vol 275 no 45 pp 35063ndash35069 2000

[239] M Kaminska V Shalak M Francin and M Mirande ldquoViralhijacking of mitochondrial lysyl-tRNA synthetaserdquo Journal ofVirology vol 81 no 1 pp 68ndash73 2007

[240] L A Stark and R T Hay ldquoHuman immunodeficiency virustype 1 (HIV-1) viral protein R (Vpr) interacts with Lys-tRNAsynthetase implications for priming of HIV-1 reverse transcrip-tionrdquo Journal of Virology vol 72 no 4 pp 3037ndash3044 1998

[241] L Q Qiu P Cresswell and K C Chin ldquoViperin is required foroptimal Th2 responses and T-cell receptor-mediated activationof NF-120581B and AP-1rdquo Blood vol 113 no 15 pp 3520ndash3529 2009

[242] X Wang E R Hinson and P Cresswell ldquoThe interferon-inducible protein viperin inhibits influenza virus release byperturbing lipid raftsrdquo Cell Host and Microbe vol 2 no 2 pp96ndash105 2007

[243] J Y Seo R Yaneva E R Hinson and P Cresswell ldquoHumancytomegalovirus directly induces the antiviral protein viperinto enhance infectivityrdquo Science vol 332 no 6033 pp 1093ndash10972011

[244] S Kim H Y Kim S Lee et al ldquoHepatitis B virus X proteininduces perinuclear mitochondrial clustering in microtubule-and dynein-dependentmannersrdquo Journal of Virology vol 81 no4 pp 1714ndash1726 2007

[245] Y Nomura-Takigawa M Nagano-Fujii L Deng et al ldquoNon-structural protein 4A of Hepatitis C virus accumulates onmitochondria and renders the cells prone to undergoingmitochondria-mediated apoptosisrdquo Journal of General Virologyvol 87 no 7 pp 1935ndash1945 2006

[246] J S Radovanovic V Todorovic I Boricic M Jankovic-Hladniand A Korac ldquoComparative ultrastructural studies on mito-chondrial pathology in the liver of AIDS patients clustersofmitochondria protuberances ldquominimitochondriardquo vacuolesand virus-like particlesrdquoUltrastructural Pathology vol 23 no 1pp 19ndash24 1999

[247] G Rojo M Chamorro M L Salas E Vinuela J M Cuezvaand J Salas ldquoMigration of mitochondria to viral assembly sitesin African swine fever virus-infected cellsrdquo Journal of Virologyvol 72 no 9 pp 7583ndash7588 1998

[248] D C Kelly ldquoFrog virus 3 replication electron microscopeobservations on the sequence of infection in chick embryofibroblastsrdquo Journal of General Virology vol 26 no 1 pp 71ndash861975

[249] R S Fujinami and M B A Oldstone ldquoAmino acid homologybetween the encephalitogenic site of myelin basic protein andvirusmechanism for autoimmunityrdquo Science vol 230 no 4729pp 1043ndash1045 1985

[250] A P Kohm K G Fuller and S D Miller ldquoMimicking the wayto autoimmunity an evolving theory of sequence and structuralhomologyrdquo Trends in Microbiology vol 11 no 3 pp 101ndash1052003


[251] M Monne A J Robinson C Boes M E Harbour I MFearnley and E R S Kunji ldquoThe mimivirus genome encodes amitochondrial carrier that transports dATP and dTTPrdquo Journalof Virology vol 81 no 7 pp 3181ndash3186 2007

[252] H A Saffran J M Pare J A Corcoran S K Weller and JR Smiley ldquoHerpes simplex virus eliminates host mitochondrialDNArdquo EMBO Reports vol 8 no 2 pp 188ndash193 2007

[253] J A Corcoran H A Saffran B A Duguay and J R SmileyldquoHerpes simplex virus UL125 targets mitochondria through amitochondrial localization sequence proximal to the N termi-nusrdquo Journal of Virology vol 83 no 6 pp 2601ndash2610 2009

[254] A Wiedmer P Wang J Zhou et al ldquoEpstein-Barr virusimmediate-early protein Zta co-opts mitochondrial single-stranded DNA binding protein to promote viral and inhibitmitochondrial DNA replicationrdquo Journal of Virology vol 82 no9 pp 4647ndash4655 2008

[255] K Machida K T Cheng C K Lai K S Jeng V M Sungand M M C Lai ldquoHepatitis C virus triggers mitochondrialpermeability transition with production of reactive oxygenspecies leading to DNAdamage and STATS activationrdquo Journalof Virology vol 80 no 14 pp 7199ndash7207 2006

[256] C de Mendoza L Martin-Carbonero P Barreiro et al ldquoMito-chondrial DNAdepletion inHIV-infected patients with chronichepatitis C and effect of pegylated interferon plus ribavirintherapyrdquo AIDS vol 21 no 5 pp 583ndash588 2007

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Mitochondria contain a single 16 kb circular DNAgenome which codes for 13 proteins (mostly subunits of res-piratory chains I II IV and V) 22 mitochondrial tRNAs and2 rRNAs [25 26]Themitochondrial genome is not enveloped(like nuclear envelop) contains few introns and does notfollow universal genetic code [27] Although the majority ofthe mitochondrial proteins are encoded by nuclear DNA andimported into the mitochondria (reviewed by [21 28ndash31])mitochondria synthesize few proteins that are essential fortheir respiratory function [1 27]

Proteins destined to mitochondria have either internallylocalized [28] or amino terminal localized [21] presequencesknown as mitochondriamatrix localization signals (MLS)which can be 10ndash80 amino acid long with predominantlypositively charged amino acids The combination of thesepresequences with adjacent regions determines the local-ization of a protein in respective mitochondrial compart-ments The outer mitochondrial membrane contains twomajor translocators namely (a) the translocase of outermembrane (TOM) 40 which functions as an entry gate formost mitochondrial proteins with MLS and (b) sorting andassembly machinery (SAM) or translocase of 120573-barrel (TOB)protein which is a specialized insertion machinery for beta-barrel membrane proteins [32] Once proteins pass throughthe outer membrane they are recruited by presequencetranslocase-associated motor (PAM) to the translocase of theinner mitochondrial membrane (TIM) 23 complexes whichmediates the import of proteins to the matrix Finally thepresequences are cleaved in matrix and proteins are modifiedto their tertiary structure and rendered functional [30]

12 Viruses Viruses are acellular obligate intracellularmicro-organisms that infect the living cellsorganisms and are theonly exception to cell theory proposed by Schleiden andSchwann in 18381839 [33] The viruses have an outer proteincapsid and a nucleic acid core Usually the viral nucleic acidscan be either DNA (double or single stranded) or RNA (+or minus sense single stranded or double stranded RNA) Someof the viruses are covered with an envelope embedded withglycoproteinsThe viruses have long been associated with theliving organisms and it was in the later part of the centurythat their relationship with various cellular organelles wasstudied in detail In order to survive and replicate in the cellviruses need to take control of the various cellular organellesinvolved in defense and immune processesThey also requireenergy to replicate and escape from the cell Once inside thehost cell they modulate various cellular signal pathways andorganelles including mitochondria and use them for theirown survival and replication This review summarizes thefunctions of mitochondria and how viruses modulate them(Figure 1)

2 Viruses Regulate Ca2+

Homeostasis in Host Cells

21 Ca2+ Homeostasis Ca2+ is one of the most abundant andversatile elements in the cell and acts as a second messen-ger to regulate many cellular processes [34] Earlier outermembrane of mitochondria was thought to be permeable to

Ca2+ but recent studies suggest that the outer membranecontains voltage-dependent anion channels (VDAC) havingCa2+ binding domains which regulate the entry of Ca2+into the mitochondrial intermembrane space [35ndash37] Theinflux of Ca2+ through the inner membrane is regulatedby the mitochondrial Ca2+ uniporter (MCU) which is ahighly selective Ca2+ channel that regulates the Ca2+ uptakebased onmitochondrialmembrane potential (MMP)Thenetmovement of charge due to Ca2+ uptake is directly propor-tional to the decrease ofMMP [38] A secondmechanism thathelps in Ca2+ movement across the mitochondria membraneis called ldquorapid moderdquo uptake mechanism (RaM) [39] In thisprocess Ca2+ transports across themitochondrial membraneby exchange with Na+ which in turn depends upon itsexchange with H+ ion and thus MMP This ion exchangeacross the mitochondrial membrane decreases MMP and isdependent on electron transport chain (ETC) for its mainte-nance A third mechanism involves IP

3R a Ca2+ channel in

endoplasmic reticulum IP3R is connected to mitochondrial

VDAC through a glucose regulating protein 75 (GRP75)This junction regulatesfacilitates Ca2+ exchange from IP

3R

to VDAC [40]Ca2+ efflux mechanism is regulated by the permeability

transition pore (PTP) The PTP is assembled in the mito-chondrial inner and outer membranes [41 42] with Ca2+binding sites on the matrix side of the inner membrane ThePTP regulates the mitochondrial Ca2+ release by a highlyregulated ldquoFlickeringrdquo mechanism that controls the openingand closing of the pore [43] RaM works in sync withryanodine receptor (RyR) isoform 1 which is another veryimportant calcium release channel [44] Both RyR and RaMregulate the phenomenon of excitation-metabolism couplingin which cytosolic Ca2+ induced contraction is matchedby mitochondrial Ca2+ stimulation of ox-phos [45] How-ever mitochondrial Ca2+ overload can result in prolongedopening of the pore leading to pathology [46] AlthoughCa2+ is involved in the activation of many cellular processesincluding stimulation of the ATP synthase [47 48] allostericactivation of Krebs cycle enzymes [49 50] and the adeninenucleotide translocase (ANT) [51] the primary role of mito-chondrial Ca2+ is in the stimulation of ox-phos [52ndash54]Thusthe elevated mitochondrial Ca2+ results in up regulation ofthe entire ox-phos machinery which then results in fasterrespiratory chain activity and higher ATP output which canthen meet the cellular ATP demand Ca2+ also upregulatesother mitochondrial functions including activation of N-acetylglutamine synthetase to generate N-acetylglutamine[55] potent allosteric activation of carbamoyl-phosphatesynthetase and the urea cycle [56] Thus any perturbationinmitochondrial or cytosolic Ca2+ homeostasis has profoundimplications for cell functionMoreovermitochondrial Ca2+particularly at high concentrations experienced in pathologyappears to have several negative effects on mitochondrialfunctions [57]

22 Regulation by Viruses A number of viruses alter theCa2+regulatory activity of the cell for their survival Herpes


HCV)


Uniporter



RyR


ER

II

IIIIV

I

ROS




VDAC

ER stress

MAVS


Cleavageat C-508


14-3-3

Bad

Caspase 9

Caspase 3

Apoptosis




(eg HSV-1 and


Caspase 8

Pre

ProCaspase 7

ProCaspase 7


(eg mimivirus)


(eg HIV and HCMV)

ATP

Cytoplasm

Nucleus

Mitochondria

Cell membrane

CARDCARDCARD


Cristae

Matrix


Ca2+

IP3R


CARDCARDCARD

PTP

O2


HSVdarr)






















2


2




2
































































11 Conclusions


Acknowledgments


References




















































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


HCV)


Uniporter



RyR


ER

II

IIIIV

I

ROS




VDAC

ER stress

MAVS


Cleavageat C-508


14-3-3

Bad

Caspase 9

Caspase 3

Apoptosis




(eg HSV-1 and


Caspase 8

Pre

ProCaspase 7

ProCaspase 7


(eg mimivirus)


(eg HIV and HCMV)

ATP

Cytoplasm

Nucleus

Mitochondria

Cell membrane

CARDCARDCARD


Cristae

Matrix


Ca2+

IP3R


CARDCARDCARD

PTP

O2


HSVdarr)






















2


2




2
































































11 Conclusions


Acknowledgments


References




















































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology










2


2




2
































































11 Conclusions


Acknowledgments


References




















































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






















































11 Conclusions


Acknowledgments


References




















































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

























































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article viruses as modulators of mitochondrial...

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