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Mitochondria and Viruses
 

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Mitochondria and Viruses

 

 
Sanjeev K. Anand
Vaccine and Infectious Disease Organization and
Dept. of Veterinary Microbiology
University of Saskatchewan
for: Advanced Virology (VTMC 833)
sanjeev.anand@usask.ca
 
                                                                                             2007
 


 

Abstract
 
Mitochondria are multifunctional organelles with diverse roles including energy production and distribution, apoptosis, eliciting host immune response, diseases and aging. This makes them a target of almost all the invading pathogens including viruses. Viruses either induce or inhibit various processes started by mitochondria in response to viral invasion in a highly specific manner to meet their ends like replication and multiplication. Many viruses encode the Bcl2 homologues to counter the pro-apoptotic functions of the cellular and mitochondrial proteins. Many of these viruses modulate the permeability transition pore and either prevent or induce the release the apoptotic proteins from the mitochondria. Viruses like herpes viruses deplete the host mitochondrial DNA and some like HIV hijack the host mitochondrial proteins to function fully inside the host cell. Interestingly most of the viral proteins targeting mitochondria lack a consensus signal maybe to prevent cells to come up with a strategy to counter their attack. Mitochondria mediated immune responses might be an evolutionary adaptation by which mitochondria might have prevented the entry of invading micro-organisms thus establishing themselves as an integral part of the cell.

 
Introduction

 
Mitochondria are cellular organelles found in the cytoplasm of almost all eukaryotic cells. One of their important functions is to produce and provide to the cell the energy in the form of ATP for proper maintenance of the cellular processes. Mitochondria perform various other functions which make them absolutely indispensable to the cell. Besides acting as a power house of the cell, they act as a common platform for the execution of a variety of cellular functions in normal cells and in cells under attack from microorganisms like viruses. Mitochondria have been implicated in aging (1-3) apoptosis (1, 4-8), the regulation of metabolism (9-11), cell-cycle control (12-15), development (16-18), antiviral responses (19), signal transduction (20) and diseases (21-24). Although, all mitochondria have the same architecture, they vary greatly in shape and size. The outer membrane, which is smooth, is a simple phospholipids bilayer containing four different types of proteins imbedded in it (25). Most important of them are the porins which allow transport (export and import) of the mitochondrial proteins, ions, nutrients and ATP etc across the membranes. The porins are permeable to molecules of about 10 kilo Dalton (kD) or less. The outer membrane surrounds the inner membrane which is highly convoluted. These convoluted structures are called cristae. Besides increasing the surface area of the membrane, they are the seat of respiratory complexes. The inner membrane of mitochondria allows free transport of water, oxygen and carbon dioxide only. The outer and the inner membranes thus create two compartments viz., the inter-membrane space and the matrix. The intermembrane space contains molecules such as Cyt C, SMAC/Diablo, endonuclease G etc. It also acts as a buffer zone between the inner and the outer membranes. The matrix contains enzymes for the aerobic respiration, dissolved oxygen, water, carbon dioxide, and the recyclable intermediates that serve as energy shuttles and perform other functions.

The majority of the mitochondrial proteins are encoded by nuclear DNA and are imported into the mitochondria by different mechanisms (reviewed by (25). However, the mitochondria do synthesize some of the proteins essential for their respiratory function (26, 27). The mitochondrion contains a single 16 kb circular DNA genome which codes for into 13 proteins (mostly subunits of respiratory chains I, II, IV & V), 22 mitochondrial tRNAs and 2 rRNAs. The mitochondrial genome is not enveloped and contains few introns. Some codons do not follow universal genetic code. Mutations in mitochondrial DNA (mtDNA) have been implicated in aging (1) and other diseases.

Viruses are acellular obligate intracellular organisms that infect the living cells/organisms and are the only exception to cell theory proposed by Schleiden and Schwann in 1838/1839 (28), which states that organisms are made up of one or more cells and cells are the basic unit of life. The viruses have an outer protein capsid and a nucleic acid core. The viral nucleic acids can be either DNA (double or single stranded) or RNA (+ or – sense ssRNA or double stranded RNA) but never both. Some of the viruses are covered with an envelop embeded with glycoproteins. The viruses have long been associated with the living organisms and it was in the later part of the century that their relationship with various cellular organelles has been studied in detail. Viruses upon entry, in order to survive and replicate, need to take control of the various cellular organelles that carry out defense and immune processes. They also require energy to replicate and escape from cell. They have to evade the immune mechanisms and also prevent apoptosis, which is programmed cell death in response to various stimuli that a cell receives. Once inside the host cell they orchestrate various signal pathways and use them for their own benefit of survival and replication. Some of these processes are discussed in this review.

 
Viruses causing apoptosis
 

Interference in mitochondrial function can cause either cell death through ATP depletion and deregulation of the Ca2+ signaling pathways or apoptosis through regulation of Bcl-2 family proteins. Apoptosis is a programmed cell death (29) characterized by membrane blebbing, condensation of the nucleus and cytoplasm, and endonucleosomal DNA cleavage. The process starts as soon as cell gets either physiological or stress stimuli disturbing the homeostasis of the cell (30). Apoptotic cell death can be considered an innate response to limit the growth of the viruses and other micro organisms attacking the cell. Two major pathways by which apoptosis gets triggered are the extrinsic and the intrinsic (31). The extrinsic pathway is mediated by signaling through death receptors like tumor necrosis factor or Fas ligand receptor. This causes the assembly of death inducing signaling complex (DISC) with the recruitment of other proteins like caspases finally leading to the mitochondrial membrane permeabilization (MMP). In apoptosis induced by the intrinsic pathway, the signals act directly on the mitochondria leading to mitochondrial membrane permeabilization before caspases are activated causing the release of Cyt C (32) which then recruits APAF1 (33) resulting in direct activation of caspase 9 (34, 35). Both the extrinsic and the intrinsic processes congregate at the activation of downstream effector caspases, like caspase-3 (36) that is responsible for many of the morphological changes characteristic of apoptosis. In addition to Cyt C, other activators of the caspases like the Smac/ DIABLO, as well as the caspase independent death effectors like apoptosis inducing factor (AIF) and endonuclease G are also released simultaneously (37-39). Another notable change observed during apoptosis is a loss of the electrochemical potential across the inner membrane (40) due to sudden opening of the permeability transition (PT) pore. The PT pore consists of three components viz., voltage dependent anion carrier (VDAC) in outer mitochondrial membrane, the adenine nucleotide transporter (ANT) in the inner membrane and cyclophilin D (CPD) associated with the matrix surface of the ANT (41, 42).
 
The Bcl-2 family of proteins tightly regulates the apoptotic events involving mitochondria (43-45). More than 20 mammalian Bcl-2 family proteins have been described to date (Table I). They have also been classified by the presence of Bcl-2 homology (BH) domains in their structure arranged in the order BH4-BH3-BH2-BH1 and the C terminal hydrophobic transmembrane (TM) domain which anchors them to the outer mitochondrial membrane (46). The BH1 and BH2 domains are highly conserved and are responsible for anti-apoptotic activity and multimerization of Bcl-2 family proteins. The BH3 domain is mainly responsible for pro-apoptotic activity and the less conserved BH4 domain is required for the anti-apoptotic activities of Bcl-2 and Bcl-XL (46). Most of the anti-apoptotic proteins contain all four BH and TM domains whereas pro-apoptotic proteins are characterized by presence of BH3 and absence of BH4 domain with or without other domains. The Bcl-2 proteins up or down regulate the MMP depending upon weather they belong to the pro or anti-apoptotic branch of the family respectively (reviewed by (43). The MMP marks the dead end of apoptosis beyond which cells are destined to die (47-51). (Figure 1)

The viruses, during their co-evolution with the hosts, have developed several strategies to manipulate the host cell machinery for their survival, replication and release from the cell. Many viruses inhibit (52) or induce (53) apoptosis for the obvious purposes of replication and spread respectively (52). Viruses target the apoptotic machinery at critical points to meet their ends.

 
Bcl-2 homologues encoded by the viruses

 
Viral Bcl-2 (vBcl-2) homologous proteins are thought to counteract apoptosis triggered by the natural host defenses in response to unscheduled growth signals provided by viral transcription activators and other internal stress signals triggered by host cell upon infection. During primary infection, vBcl-2 enhances the lifespan of the host cells resulting in higher numbers of viral progeny and ultimately spread of infection to the new cells. The expression of vBcl-2 proteins also favors viral persistence in cell by enabling the latently infecting viruses to make the transition to productive infection. With the exception of the Epstein–Barr virus (EBV) BALF1 protein, most other vBcl-2 homologues prolong the life of a cell. These Bcl-2 homologues have domains characteristic of the human Bcl-2 family of proteins. While the vBcl-2s and the cellular Bcl-2s share limited sequence homology, their secondary structures are predicted to be quite similar (54).

Many viruses code for the anti-apoptotic Bcl-2 homologues which preferentially localize to the mitochondria and may interact with the other pro-apoptotic Bax homologues. The EPV, a human herpes virus, codes for BHRF1, an early protein, which localizes to the mitochondrial outer membrane and co-localizes with Bcl-2 (55, 56). The BHRF1 interacts with the cellular protein VRK2 (57) and enhances the cell survival. The EBV encodes another Bcl-2 homologue BALF1, which interacts with the Bax and Bak (58) and inhibits the anti-apoptotic activity of the BHRF1 and the Kaposi Sarcoma Bcl-2 (KSBcl-2) (59). BLAF1 lacks pro-apoptotic activity and thus acts as a negative regulator of the survival function of the BHRF1. Other herpes viruses also encode the Bcl-2 homologues. Herpesvirus saimiri-encoded Bcl-2 homolog (HVS-Bcl-2) acts upstream of the caspases 3, stabilizes mitochondria against a variety of apoptotic stimuli and prevents the cell death (60). Most of these Bcl-2 homologues prevent MMP much like their cellular counterparts, where BH4 domain of the Bcl-2 interacts with VDAC and prevents it from forming protein-permeable conduits (61). Many of the virus encoded Bcl-2 homologues, like the adenovirus E1B19K (62), lack BH4 domain and are thought to act by inhibiting pro-apoptotic members of Bcl-2 family proteins. E1B19K predominantly localizes to the nuclear lamina in non-apoptotic cells. Treatment of infected cells with tumor necrosis factor (TNF) or transfection with the tBID, causes translocation of E1B19K to the mitochondria, together with Bax, and prevents the Bax/t-Bid-mediated MMP, most probably by local effects on Bax. TNF-alpha-mediated death signaling is also blocked by E1B19K by inhibiting a form of Bax that interrupts the caspase activation downstream of caspase-8 and upstream of caspase-9 (62).

African swine fever virus (ASFV) codes an anti-apoptotic Bcl-2 homologue 5-HL, which is a survival factor for virus during infections (63). It is a highly conserved gene (of the family Asfaviridae) which contains all the domains (BH1, BH2 and BH3) characteristic of human Bcl-2 proteins and has a very high anti-apoptotic properties (63). Another ASFV protein A179L, which is similar to the human proto-oncogene Bcl-2, prevents the apoptosis induced by interferon-induced double-stranded RNA-activated protein kinase (64).

The hepatitis B virus (HBV) also has a Bcl-2 homology domain 3 (BH3), which interacts with anti-apoptotic factors in the cell and induces the apoptosis (65). It localizes to mitochondria where it interacts with VDACs and induces the loss of the electrochemical potential (66). The effects of viral Bcl-2 homologues are thus apparently centered on mitochondria and include prevention or induction of MMP loss and in latter case release of Cyt C and other pro-apoptotic signals into cytosol and activation of downstream caspases leading to cell death.

 
Viral proteins altering the mitochondrial membrane potential
 
 
Activity of the permeability transition pore (PTP) determines the activity of pro-apoptotic proteins. When open, it results in increased permeability of inner membrane to ions and solutes upto 1500 daltons (Da), which causes dissipation of the mitochondrial membrane potential and diffusion of solutes down their concentration gradients, by a process known as the permeability transition. (67, 68). PTP opening is followed by osmotic water flux, passive swelling, outer membrane rupture, and Cyt C release (67). PTP is inhibited by Cyclosporin A (CsA) and is also regulated by a striking number of modulators (e.g., voltage, matrix Ca2+, matrix pH, redox potential) and signaling molecules (such as arachidonic acid and complex lipids) that are also involved in cell death (41, 69). Because of the consequent depletion of ATP and Ca2+ deregulation, opening of the PTP had been proposed to be a key element in determining the cell fate before a role for mitochondria in apoptosis was discovered (69).

The voltage dependent anionic channels (VDACs) form channels and act as the primary pathway for the movement of metabolites across the outer membrane (70, 71). Purified and reconstituted VDAC forms anion-selective channels with an open channel diameter of 3nm. When positive or negative voltages are applied, VDAC closes to form cation-selective channels with a smaller diameter and lower conductance (70).

Adenine nucleotide translocator (ANT) (72), is an inner membrane protein that catalyzes the exchange of the ATP for the ADP and permits the export of ATP from respiring, energized mitochondria (73). The evidence linking the ANT to the permeability transition is basically based on the effects of atractylate and bongkrekate. Atractylate favors the permeability transition while bongkrekate inhibits it but both of them inhibit ATP-ADP exchange catalyzed by ANT. Studies on liver mitochondria obtained from ANT-knockout mice revealed that the ANTs are non-essential components of the mitochondrial PTP (74) and that they are dispensable for at least some forms of the mitochondrial PTP-associated cell death. These studies further revealed that the ANTs do have an essential role in regulating permeability transition by modulating the sensitivity of the mitochondrial PTP to the Ca2+ activation and the ANT ligands. Exact role of ANTs remains controversial though (75) Many viral proteins that alter mitochondrial ion permeability and/or membrane potential have been identified. Most prominent of these are discussed below:

The role of Hepatitis B protein X (HB-X) in inducing or preventing the apoptosis was controversial untill two independent studies (66, 76) characterized its ability to localize to mitochondria and bind to the VDACs. Both of these studies showed that HB-X induced apoptotic changes including perinuclear clustering of the mitochondria, MMP and electrochemical potential loss and DNA damage. In contrast, another study revealed the protective effects of HB-X in response to pro-apoptotic stimuli (Fas, TNF and serum withdrawal) (77). It was found that HB-X favors survival of the cell under low serum conditions, but not from chemical apoptotic stimuli. It also prevents caspase 8 and 3 activation, and translocation of Cyt C into cytosol. Co-imunoprecipitation studies showed its localization in MEKK1, SEK1, SAPK, and 14-3-3 complex indicating its role in cell survival. HB-X is also known to stimulate NFκB (78, 79), SAPK(80, 81) and PI3K/PKB (82) cell survival pathways. It also interacts with mitochondrial HSP60 (83) to induce apoptosis. It is unknown whether all these interactions occur simultaneously indicating the diverse functions a small protein promoting the survival of virus inside the cell.

Hepatitis C virus (HCV) causes the ROS mediated damage to mitochondria and lowers the MMP which can be inhibited by treatment with Bcl-2. N-acetyl-L-cysteine (NAC), an inhibitor of ROS production, or an inhibitor of NO- the 1400W - can prevent the changes in MMP, thereby indicating the involvement of these species in induction of mitochondria mediated apoptosis via PTP (84). The P7, a hydrophobic, integral membrane (85) viroprotein (86) of HCV is targeted to mitochondria. (87) P7 assembles into hexameric complexes both in artificial membranes and in cells. It controls membrane permeability to cations (87, 88) and promotes replication by aiding entry and release of viral particles (86).

Viral mitochondrial inhibitor of apoptosis (vMIA), a splice variant of UL37 of human cytomegalovirus (HCMV) (89), has also been shown to protect the cells from the apoptosis. It localizes to mitochondria and interacts with ANT (89) and Bax (90, 91). vMIA has a N-terminal mitochondrial localization domain and a C-terminal anti-apoptotic domain (89) which recruits Bax to mitochondria and prevents MMP. It protects the cells against CD95 ligation (89), over expression of Bid (91), staurosporine (90) and oxidative stress induced cell death (92, 93). It also prevents mitochondrial fusion and disrupts the reticular morphology of the mitochondria (94) indicating the protective role of vMIA. In Bax negative cells, overexpression of vMIA destroys the mitochondrial network which indicates that Bax is not involved in vMIA mediated alteration of mitochondrial morphology. vMIA can not inhibit the apoptotic events upstream of mitochondria but can influence events like preservation of ATP generation, inhibit Cyt C release and caspase 9 activation, following induction of apoptosis. This supports the hypothesis that it might act at PTP level to regulate the apoptosis. Exact mechanisms of events around vMIA still remain an enigma.

Human immunodeficiency virus (HIV) protein R (Vpr) is a small accessory protein which localizes to mitochondria and has pro-apoptotic activities (95, 96). It promotes MMP, Cyt C release (97) and cell death by modulating PT pore. The C-terminal of Vpr has several arginine residues which are critical for modulation of MMP (96) by interaction with ANT. Mutants lacking functional ANT or cells infected with mutated Vpr fails to induce the MMP and cell death (96). The functional interaction between ANT & Vpr is inhibited by Bcl-2 while Bax has antagonistic effect (47, 96) (Figure 2). Further, Vpr increases the activation of the caspases 3 and 9 but not 8 (97). This suggests that Vpr is a virulent factor in HIV-1 infection.

HIV-1 protein Tat also sensitizes cells to PTP mediated apoptosis. In a stable-transfected HIV-Tat cell lines, cells are primed to undergo apoptosis upon serum withdrawal (98). The apoptosis is caspase dependent and is associated with Tat accumulation on mitochondria and MMP loss. It  also causes an increased production of ROS. Moreover Tat has been  found to synergize with protoporphyrin IX (PPIX), a ligand of the mitochondrial benzodiazepine receptor, in the induction of apoptosis, demonstrating the involvement of PT pore (98).

Orf C protein of Walleye dermal sarcoma virus (WDSV) also localizes to mitochondria. Over expression of Orf C causes perinuclear clustering of mitochondria and loss of membrane potential (99) leading to release of pro-apoptotic factors thus causing apoptosis.

Myxoma pox virus protein M11L exerts its anti-apoptotic effects during viral infection. (100). Expression of M11L in cells alone revealed its localization to mitochondria and its ability to induce caspases 3 and DNA fragmentation upon stimulus form staurosporine. It inhibits MMP loss upon localization to mitochondria (101). M11L physically associates with the mitochondrial peripheral benzodiazepine receptor (PBR) and directly regulates the mitochondrial permeability transition pore complex, most likely by direct modulation of the PBR (102), a component of the PTP.

Human papilloma virus (HPV) type 16 protein E6 also sensitizes cells to atractyloside induced apoptosis. Atractyloside is an ANT ligand, which induces PTP opening and MMP loss (103). The effect can be reversed by cyclosporine A, a PTP blocker, indicating its direct involvement in the process. The effect is both p53 and caspases dependent (103). E6 proteins from HPV down regulate signals upstream of mitochondria like Bak (104, 105) and prevent the release of Cyt C, AIF and Omi, thus preventing apoptosis (106). This E6 activity towards Bak is a key factor promoting the survival of HPV-infected cells which in turn facilitates the tumor development.

Vaccinia virus codes a protein F1L, which interferes with apoptosis by inhibiting the loss of the inner mitochondrial membrane potential and the release of Cyt C (107) by down regulation of Bak (108), a pro-apoptotic Bcl-2 family protein. It also inhibits the Bax activity preventing its oligomerization and N-terminal activation by interacting directly with its upstream protein BimL (109). F1L is a tail anchored protein with C-terminal hydrophobic tail which is responsible for the mitochondrial targeting and anti-apoptotic function. The C-terminal tail also shares slight homology with the C-terminal of Bcl-2 (110). Also, pox viruses encoded crmA/Spi-2, a caspase 8 inhibitor, has been found to modulate PT pore and thus prevent apoptosis (111).

Influenza A viruses code for a protein PB1-F2, which targets mitochondria (112). It has a C-terminal mitochondria localization signal, which is conserved in the influenza family (113, 114). The protein localizes to mitochondria resulting in the alteration of mitochondrial morphology, dissipation of mitochondrial membrane potential, and cell death. PB1-F2 protein interacts directly with VDAC1 and ANT3 (115) (Figure) and decreases MMP, which results in the release of pro-apoptotic proteins thereby causing cell death.  Influenza virus also codes for a viroprotein M2, similar to p7 coded by HCV (reviewed by 86).

An accessory protein, p13II , of human T-lymphotropic virus (HTLV), a 87 amino acid long protein coded by x-II ORF, localizes to mitochondria upon infection (116). Further studies revealed that this protein alters the mitochondrial membrane permeability leading to apoptosis. Expression of this protein also results in the disruption of mitochondrial network into isolated clusters of round-shaped mitochondria, a pattern suggestive of mitochondrial swelling (116). These changes were confirmed later by electron microscopy revealing fragmentation of cristae and swelling (117-119). Moreover, mitochondria exhibiting more prominent changes were found in close proximity to endoplasmic reticulum. The ability of p13II to alter the mitochondrial ion transport in vitro and disrupt their morphology in intact cells require a “functional domain” (residues 9–41) that includes the MTS and is strictly dependent on the presence of arginines 22, 25, 29, and 30 constituting the charged face of p13II's α-helix (120).

 
Non specific targets/ events

 
Various other viral proteins interact with mitochondria and they either induce or prevent the cell death. Other than Vpr and Tat, there is another HIV-1 protein found to modulate the mitochondrial activity. Stable expression of Nef (a 24 kilo Dalton protein and an essential modulator of AIDS pathogenesis) in lymphocyte cell lines has been found to sensitize cells to the loss of transmembrane potential and apoptosis induced by several chemical agents (121). This leads to reduction in expression Bcl-2 and Bcl-XL , which inhibit the activation of caspases and caspases inducing factors from mitochondria (122). This contributes to the maintenance of the proton gradient responsible for the transmemberane potential by inducing a proton efflux from mitochondria (123, 124) which explains the enhancement of apoptosis in Nef expressing cells. The caspase inhibitors can also induce cell death indicating different mechanisms by which Nef could act. Nef also stimulates the cell survival pathways (125) and act as an antiapoptotic protein. 

The E4orf4 protein of human adenovirus also activates the apoptosis in the cell. During the process, mitochondria related events (Cyt C and ROS production) require caspase 8 activation and not the caspase 9 indicating the independence of post mitochondrial events from caspases (126). Further, E4orf4 induces the accumulation of reactive oxygen species (ROS) in a caspase-8- and FADD/MORT1-dependent manner. The inhibition of ROS generation by 4,5-dihydroxy-1, 3-benzene-disulfonic acid (Tiron) inhibits E4orf4-induced apoptosis (126).

HCV core protein expression inhibits the deoxycholic acid (DCA) mediated apoptosis. DCA causes the mitochondrial transmembrane depolarization and activates caspases 9 & 3. The core protein increases the Bcl-xL protein and decreases Bax protein, without affecting the proportion of Bax between the mitochondria and the cytosol, resulting in suppression of Cyt C release from mitochondria into cytoplasm and thus inhibiting DCA-mediated apoptosis. HCV core protein also inhibits apoptosis mediated by TNF alpha (127) but sensitizes cells to Fas mediated apoptosis (128).


 
Viruses hijacking the mitochondrial proteins

 
p32 is a cellular protein, which is predominantly associated with the mitochondria. It is a member of a complex involved in the import of cytosolic proteins to the nucleus. Adenovirus upon entry into cell, hijacks this protein and piggybacks it to transport its genome to the nucleus (129).

tRNA acts as a primer to initiate the replication of HIV-I RNA gnome which binds to a site complementary to the 3'-end 18 nucleotides of tRNA3Lys. During HIV-1 assembly, tRNALys isoacceptors are selectively incorporated into virions and tRNA3Lys is used as the primer for reverse transcription (130). In humans, a single gene encodes both cytoplasmic and mitochondrial Lys tRNA synthetases (LysRSs) by alternative splicing and both of these species share 576 identical amino acid residues (131). The mitochondrial LysRSs is produced as a pre protein and is transported into mitochondria. Recent work has shown that pre-mito or mitochondrial LysRS is specifically packaged into HIV (132). In order to get into virion, it needs to be exported out of mitochondria; it is proposed that VPr alters the permeability of the mitochondria (96) leading to release of pre-mito or mito LysRS, which then interacts with Vpr (133) and gets packed into virus.

 
Viruses altering the intracellular distribution of mitochondria
 

Some of the viral proteins alter the intracellular distribution of mitochondria. Main reasons for this kind of activity can be to concentrate the mitochondria near viral factories to meet energy requirement during viral replication and/or cordon off mitochondria to prevent the release of mediators of apoptotis.
Hepatitis B protein X causes the perinuclear clustering of the mitochondria by p38 mitogen-activated protein kinase (MAPK) mediated dynein activity. HBX activates p38 MAPK which in turn up regulates the microtubule-dependent dynein activity resulting in relocalization of the mitochondria to the perinuclear space. The mitochondrial migration is appreciably affected in presence of nocodazole, a microtubule inhibiting drug, but not in presence of cytochalasin-D, an actin disrupting drug indicating the involvement of microtubules in the process (134).
    Non-structural protein 4A (NS4A) of HCV accumulates either alone or together with NS3 in the form of the NS3/4A polyprotein on mitochondria and changes their intracellular distribution. It causes change in MPP and release of Cyt C into the cytoplasm, which leads ultimately to induction of apoptosis through the activation of caspase-3, but not caspase-8 (135).

African swine fever virus (ASFV) causes the microtubule mediated clustering of the mitochondria around virus factories in the cell (136). Viral infection causes the ultra-structural changes in mitochondria with a shift towards actively respiring mitochondria indicating that the viruses require the high energy during assembly phase. It also promotes the induction of the mitochondrial stress-responsive proteins p74 and cpn 60 consistent with their altered morphology. However, the infection did not induce the biogenesis of the mitochondria. Similar changes have been observed in the chick embryo fibroblasts infected with frog virus 3, where degenerate mitochondria surrounding virus factories were found (137).

HIV 1 also causes clustering of the mitochondria in infected cells. The mitochondria become disorganized and the number of cristae is reduced. Infection also causes the formation of vacuoles in and around mitochondria, and the shrinkage of mitochondria (138). Viruse like particles were also observed at the periphery of the electron dense mitochondrial remains.

 
Viruses causing oxidative stress
 
 
HCV core protein causes the oxidative stress in the cell and alters apoptotic pathways (139). Other HCV proteins -core, E1, and NS3 - are potent ROS inducers and their expression causes the DNA damage and activation of STAT3 (84). Further HCV infection causes cellular DNA damage and mutations, which are mediated by nitric oxide (NO). NO damages mitochondria, causing double-stranded DNA breaks (DSBs) and accumulation of oxidative DNA damage.

E3 region of the adenovirus codes a 11.6KDa protein, known as adenovirus death protein (ADP), which causes efficient lyses of the cell following the replication cycle is complete, paving their way to infect the surrounding cells. Prior to cell lyses, an increase in mitochondrial activity in cells infected with wild type virus compared to ADP mutants has been observed (140) indicating that ADP exerts a synergistic effect on mitochondria and uses the energy surge for efficient cell burst and virus release.

 
Viruses mimicking the mitochondrial proteins
 

Mimivirus, a member of the newly created virus family Mimiviridae, codes a eukaryotic mitochondria carrier protein (VMC-I). Upon infecting its host this protein mimics the host cell’s mitochondrial carrier protein and thus controls the mitochondrial transport machinery and transports ADP, dADP, TTP, dTTP, and UTP in exchange for dATP. The virus may exploit the host to take care of the energy required during replication of its A+T rich genome (141). Besides VMC-I, there are five other proteins (L359, L572 , R776, R596, R740 and R824) with putative mitochondria localization signals. In addition to these, there are four other proteins (L81, R151, R900, and L908) with possible mitochondrial localization signal but their function remains elusive. A large number of mitochondrial targeting proteins suggest that virus has evolved a strategy to take over the host mitochondria and exploit its physiology to compensate for the energy requirements and biogenesis (141).

 
Host mitochondrial DNA depletion
 

 
    Herpes Simplex Virus I (HSV-I) induces the rapid and complete degradation of host mitochondrial DNA during productive infection of cultured mammalian cells (142). HSV-I proteins ICP27 (143) and UL41 (144) induce depletion of nuclear genome encoded host mRNAs, which inhibit the transcription and processing of the cellular nuclear mRNA precursors allowing viral mRNAs to take over the cellular transcription machinery. Mammalian cells also contain a small circular mitochondrial genome which synthesizes enzymes for oxidative phosphorylation and mitochondrial RNAs (mtRNAs). Herpes virus also triggers the depletion of host mtDNA following transfection with N terminal truncated UL12 isoform-UL12.5, which rapidly localizes to mitochondria and induces DNA depletion in absence of other gene products (142). UL12.5 has DNase activity but how it leads depletion of mtRNAs is not properly understood. Earlier, it was thought that HCV stimulates the mtDNA production in the infected cells (145-148) but with better understanding and better resources, mechanisms behind these previously unknown processes are becoming clear. HCV also causes the reactive oxygen species and Nitrous oxide mediated DNA damage in host mtDNA (84). In HIV/HCV co-infected hosts depletion of mtDNA was also observed.

 
Mitochondrial antiviral immunity- MAVS/ CARDIFF/ VISA/ IPF-I
 

 
Upon sensing viral attack, host cell initiates a variety of signal transduction pathways leading to the production of interferons (149), which limit or eliminate the invading virus. The cell recognizes viral attack by detecting the presence of the exogenous nucleic acids. TLR-3 recognizes viral dsRNA (150, 151) while retinoic acid-inducible gene I (RIG-I) (152) and melanoma differentiation-associated gene 5 (mda-5) (153), both RNA helicases, recognize dsRNA. The N-terminus of RIG-1 has two caspase activation and recruitment domains (CARDs) whereas C-terminus has RNA helicase activity (152) and recognizes and binds to dsRNA in ATPase dependent manner. This causes conformational changes and exposes its CARD domains to bind and activate downstream effectors leading to the formation of enhanceosome (154) triggering NFκB production.

A CARD domain containing protein has been identified recently that acts downstream of the RIG-I. This protein has been named mitochondrial anti-viral signaling protein (MAVS) (155), virus-induced signaling adaptor (VISA) (156), IFN- promoter stimulator 1 (IPS-1)(157) and CARD adaptor inducing IFN- (CARDIF) (158). Resarch indicates that the MAVS has an important role in raising the antiviral defenses in the cell. The MAVS -/- mice were severly compromised in the immune response against viruses, though they don’t show any developmental abnormality (159). Oversexpression of MAVS leads to activation of NFκB and IRF-3, leading to the induction of type I interferon response. In the absense of MAVS, this effect is abrogated (155) indicating the specific role of MAVS in inducing antiviral response. There is though no consensus that emerges from the present studies about the proteins acting downstream of MAVS to induce interferons.

Besides the N-terminal CARD domain, MAVS also contains a proline-rich region and a C-terminal hydrophobic transmembrane (TM) region which targets the protein to the mitochondrial outer membrane, which is critical for its activity (155). The TM region of the MAVS resembles the TM domains of many C-terminal tail anchored proteins on the outer memberane of the mitochondria including Bcl-2 and Bcl-xL. The cleavage from the mitochondria and/or miscloalization of MAVS to other cell organells greatly reduces its ability to induce interferons and a few viruses use this stretegy to get away from host defenses.

HCV persists by lowering the host cell immune response by expressing its proteins such as NS3/4A. It is a serine protease and inhibits the interferon beta production by RIG-I pathway (160-162). Recent studies (158, 163) show that NS3/4A protease cleaves MAVS at Cys-508, which is located a few residues before its mitochondrial targetting domain. It dislodges MAVS from the mitochondria and gets inactivated as free form of the MAVS is not functional. It was also shown that NS3/4A co-localises on the mitochondria with MAVS and can cleave it directly (163) and a mutation in C508 position with arginine can prevent the cleavage. This shows that HCV paralyses the host defence by cleaving MAVS off the mitochondria. (Figure 2)

Another member of family Flaviviridae GB virus B, which shares about 28% amino acid homology with HCV (164) cleaves MAVS at C508, in a manner similar to HCV and effectively prevents the interferon production (165). As in the case of HCV, mutation C508R failed to cleave the MAVS indicating the critical role of cystine residue in the sequence. 

 
Conclusions and Perspectives

 
Data summarized above and in figure 3 indicates that mitochondria are multifunctional organelles with diverse roles including but not limited to energy production and distribution, eliciting host immune response, apoptosis and diseases. It clearly shows that mitochondria act as one of the favorite organelle for invading viruses and many mitochondrial proteins targeted by viruses are relevant to pathogenesis of the diseases they cause (like Vpr, Nef in HIV, NS2/4A in HCV). It also tells us many ways viruses use in order to establish, replicate, release and spread to other cells and in disguise opens up the possibilities by which we can interfere these processes and devise strategies to prevent or cure the disease.

Many viruses either induce or prevent apoptosis by a variety of mechanisms by modulating various signal transduction pathways, inducing ROS formation, or inhibiting cell survival mechanisms in a highly specific manner. Whereas apoptosis inhibition involving mitochondria should exhibit broad range of cyto-protection because many pro-apoptotic signals converge there. Some viruses like CMV (vMIA and vICA) and hepatitis B virus (HBX) produce kind of proteins having both pro and anti-apoptotic activity and activate them as per their requirement in host cell. This illustrates the mechanisms by which these viruses modulate and balance the pro and anti- apoptotic process (es) to enhance their chances of survival inside the cell.

Viruses like HCV interfere in more than one process in a more than one way. This indicates that for any given viral infection there are multiple processes going on in the cell to get rid of it. A few viral proteins (like those of the HIV-I and the adenovirus) act in a non specific manner to affect the physiology of the cell for the benefit of the virus. What exactly these proteins do to cell and in viruses causing multiple effects, which of the processes take lead in the cell is still a puzzle scientist trying to solve. With the development of better techniques we may be able to answer these questions in a better way.

One more interesting fact that comes out of this review (though not discussed above) is that most of the viral proteins which are targeted to mitochondria in a way or other lack a consensus mitochondrial localization signal. The virus encoded proteins employ various strategies to localize to mitochondria with a variety of signals. This may be an effective tool to dodge host defense mechanisms as this rules out development of a single strategy by cell to destroy the incoming viral protein(s) thus keeping defense mechanisms keep guessing all the times. Role of the mitochondria in immunity and viral mechanisms to evade them also highlights the fact that even after billions of years of co-evolution, the fight for the survival is still going on and both the host and the viruses are evolving, finding new ways to survive. It is also interesting to note that mitochondria mediated apoptosis might be an evolutionary adaptation by which they might have effectively prevented the entry of other micro-organisms trying to gain entry into the host cell and thus effectively establishing themselves as an integral part of the cell.

 
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Figures
 


Figure 1: Intrinsic and extrinsic mechanisms of apoptosis. The extrinsic pathway is mediated by signaling through death receptors like tumor necrosis factor or Fas ligand receptor. This causes the assembly of death inducing signaling complex (DISC) with the recruitment of other proteins like caspases 8 & 7 which activate each other by autoproteolysis. This finally leads to the membrane permeabilization and apoptosis.

In the intrinsic pathway sensitivity of cells to apoptosis depends on the balance between pro and anti apoptotic Bcl-2 family proteins I cytoplasm and on the surface of mitochondria.  Some of these proteins (Bcl-2 and Bcl-xL) are anti-apoptotic (red inverted Ts) while others (Bad, Bax, Bid) are pro-apoptotic (green arrows). The pro-apoptotic Bcl-2 proteins are found in the cytosol where they act as sensors of cellular damage or stress while anti-apoptotic protein are localized on the surface of mitochondria. Upon virus infection pro-apoptotic proteins move and relocate to the mitochondrial surface and interact with anti-apoptotic proteins. The interaction of pro and anti apoptotic proteins leads to formation of pores through which initiators of apoptosis (Cyt C, endoG, SMAC etc) are released from intermemberane space. These molecules recruit downstream effectors to form apoptosome and the activation of caspase cascade. Eg Upon release Cyt C interacts with apaf1 which then recruits pro-caspase 9 and forms apoptosome. Apoptosome leads to caspase 9 activation which them recruits caspase 3 and leading to apoptosis.


Figure 2: The RIG-I – MAVS signaling pathway. RIG-I contains two N-terminal CARD domains (light orange) and a C-terminal RNA helicase. Helicase interacts with incoming viral RNA. MAVS/IPS-1/VISA/Cardif is a link between RIG-I and downstream kinases. Upon sensing viral RNA the CARD domains of RIG-I and MAVS/IPS-1/VISA/Cardif interact leading to the activation of TBK-1 and IKKε kinases and the phosphorylation of IRF-3 and IRF-7 transcription factors. MAVS/IPS-1/VISA/Cardif can also lead to NF-κB activation via the IKKα/β/γ complex, which phosphorylates the inhibitory subunit IκBα, resulting in the release of NF-κB DNA-binding subunits. MAVS/IPS-1/VISA/Cardif contains a mitochondrial transmembrane domain (TM) that localizes it to mitochondria. Protease activity of NS3/4A of HCV and GB virus cleaves the C-terminal domain of MAVS/IPS-1/VISA/Cardif at C508 and disrupts the RIG-I-mediated activation of IFN leading to chronic viral infections.


Figure 3:  Virus – Mitochondria interactions: This figure summarizes the events involving mitochondria following viral infections. Upon viral infection the viral Bcl-2 homologues prevent mitochondrial membrane permeabilzation (MMP) and thus prevent the release of pro-apoptotic factors like Cyt C, endo G, SMAC etc thereby prolonging the life of a viral infected cell. Some viruses (in yellow box) target the permeability transition pore and either facilitate or inhibit the release of various pro-apoptotic factors. Viruses like HIV and HCV  (purple box) along with exerting other effects described in text, destroy host mitochondrial DNA during their course of infection. Though the exact reasons for doing so are still unclear but they may do so to snub mitochondria to enhance the chances of their survival in the cell. Many of these viruses exhibit ROS mediated damage or by mimicking the activity of the mitochondrial proteins. Effects caused by viruses described above are varied and overlapping. Whether all these effects occur in sequence or in unison is still a puzzle scientist trying to solve.