Mitochondria and Viruses Biologisch Medisch Centrum Utrecht Epe Paul van Meerendonk

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.

References

1. Chan DC. Mitochondria: Dynamic organelles in disease, aging, and development. Cell. 2006 Jun 30;125(7):1241-52.
2. Gershon D. The mitochondrial theory of aging: Is the culprit a faulty disposal system rather than indigenous mitochondrial alterations? Exp Gerontol. 1999 Aug;34(5):613-9.
3. Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annu Rev Genet. 2005;39:359-407.
4. Antignani A, Youle RJ. How do bax and bak lead to permeabilization of the outer mitochondrial membrane? Curr Opin Cell Biol. 2006 Dec;18(6):685-9.
5. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007 Jan;87(1):99-163.
6. Gradzka I. Mechanisms and regulation of the programmed cell death. Postepy Biochem. 2006;52(2):157-65.
7. Gogvadze V, Orrenius S. Mitochondrial regulation of apoptotic cell death. Chem Biol Interact. 2006 Oct 27;163(1-2):4-14.
8. McBride HM, Neuspiel M, Wasiak S. Mitochondria: More than just a powerhouse. Curr Biol. 2006 Jul 25;16(14):R551-60.
9. Chen H, Chomyn A, Chan DC. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem. 2005 Jul 15;280(28):26185-92.
10. Mannella CA, Pfeiffer DR, Bradshaw PC, Moraru II, Slepchenko B, Loew LM, et al. Topology of the mitochondrial inner membrane: Dynamics and bioenergetic implications. IUBMB Life. 2001 Sep-Nov;52(3-5):93-100.
11. Hackenbrock CR. Ultrastructural bases for metabolically linked mechanical activity in mitochondria. I. reversible ultrastructural changes with change in metabolic steady state in isolated liver mitochondria. J Cell Biol. 1966 Aug;30(2):269-97.
12. Hardie DG. New roles for the LKB1-->AMPK pathway. Curr Opin Cell Biol. 2005 Apr;17(2):167-73.
13. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 2005 Apr 29;18(3):283-93.
14. Mandal S, Guptan P, Owusu-Ansah E, Banerjee U. Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in drosophila. Dev Cell. 2005 Dec;9(6):843-54.
15. Sesaki H, Jensen RE. Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J Cell Biol. 1999 Nov 15;147(4):699-706.
16. Bakeeva LE, Chentsov YS, Skulachev VP. Mitochondrial framework (reticulum mitochondriale) in rat diaphragm muscle. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1978/3/13;501(3):349-69.
17. Honda S, Hirose S. Stage-specific enhanced expression of mitochondrial fusion and fission factors during spermatogenesis in rat testis. Biochemical and Biophysical Research Communications. 2003/11/14;311(2):424-32.
18. Bakeeva LE, Chentsov YS, Skulachev VP. Intermitochondrial contacts in myocardiocytes. Journal of Molecular and Cellular Cardiology. 1983/7;15(7):413-20.
19. Seth RB, Sun L, Chen ZJ. Antiviral innate immunity pathways. Cell Res. 2006 Feb;16(2):141-7.
20. Bossy-Wetzel E, Barsoum MJ, Godzik A, Schwarzenbacher R, Lipton SA. Mitochondrial fission in apoptosis, neurodegeneration and aging. Current Opinion in Cell Biology. 2003/12;15(6):706-16.
21. McFarland R, Taylor RW, Turnbull DM. Mitochondrial Disease—Its impact, etiology, and pathology. In: Justin C. St. John, editor. Current Topics in Developmental Biology. Academic Press; 2007. p. 113-55.
22. Olanow CW, Tatton WG. ETIOLOGY AND PATHOGENESIS OF PARKINSON'S DISEASE. Annu Rev Neurosci 1999;22(1):123-44.
23. Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, et al. Incidence of parkinson's disease: Variation by age, gender, and race/ethnicity. Am J Epidemiol. 2003 Jun 1;157(11):1015-22.
24. Martin LJ. Mitochondriopathy in parkinson disease and amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2006 Dec;65(12):1103-10.
25. Rapaport D. Finding the right organelle. targeting signals in mitochondrial outer-membrane proteins. EMBO Rep. 2003 Oct;4(10):948-52.
26. Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annu Rev Genet 2005;39(1):359-407.
27. Burger G, Gray MW, Franz Lang B. Mitochondrial genomes: Anything goes. Trends in Genetics. 2003/12;19(12):709-16.
28. Schwann T. Microscopical researches into the accordance in the structure and growth of animals and plants. In: Schleiden MJ, editor. Contributions to phytogenesis. 1st English edition ed. London: Sydenham Society; 1847. p. xx-268.
29. Kerr JF, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239-57.
30. Gulbins E, Dreschers S, Bock J. Role of mitochondria in apoptosis. Exp Physiol. 2003 January 1;88(1):85-90.
31. Sanfilippo CM, Blaho JA. The facts of death. Int Rev Immunol. 2003 Sep-Dec;22(5-6):327-40.
32. Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell. 1996 Jul 12;86(1):147-57.
33. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997 Aug 8;90(3):405-13.
34. Green DR. Apoptotic pathways: The roads to ruin. Cell. 1998 Sep 18;94(6):695-8.
35. Sun XM, MacFarlane M, Zhuang J, Wolf BB, Green DR, Cohen GM. Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem. 1999 Feb 19;274(8):5053-60.
36. Ashkenazi A, Dixit VM. Death receptors: Signaling and modulation. Science. 1998 Aug 28;281(5381):1305-8.
37. Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol. 2001 Nov;3(11):E255-63.
38. Ohta S. A multi-functional organelle mitochondrion is involved in cell death, proliferation and disease. Curr Med Chem. 2003 Dec;10(23):2485-94.
39. Luigi Ravagnan, Thomas Roumier,Guido Kroemer,. Mitochondria, the killer organelles and their weapons. J Cell Physiol. 2002;192(2):131-7. Available from: http://dx.doi.org/10.1002/jcp.10111.
40. Zamzami N, Kroemer G. The mitochondrion in apoptosis: How pandora's box opens. Nat Rev Mol Cell Biol. 2001 Jan;2(1):67-71.
41. Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999 Jul 15;341 ( Pt 2)(Pt 2):233-49.
42. Rasola A, Bernardi P. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis. 2007 Feb 6.
43. Lucken-Ardjomande S, Martinou JC. Regulation of bcl-2 proteins and of the permeability of the outer mitochondrial membrane. C R Biol. 2005 Jul;328(7):616-31.
44. Harris MH, Thompson CB. The role of the bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ. 2000 Dec;7(12):1182-91.
45. Reed JC, Jurgensmeier JM, Matsuyama S. Bcl-2 family proteins and mitochondria. Biochim Biophys Acta. 1998 Aug 10;1366(1-2):127-37.
46. Scorrano L, Korsmeyer SJ. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun. 2003 May 9;304(3):437-44.
47. Brenner C, Cadiou H, Vieira HL, Zamzami N, Marzo I, Xie Z, et al. Bcl-2 and bax regulate the channel activity of the mitochondrial adenine nucleotide translocator. Oncogene. 2000 Jan 20;19(3):329-36.
48. Belzacq AS, Vieira HL, Verrier F, Vandecasteele G, Cohen I, Prevost MC, et al. Bcl-2 and bax modulate adenine nucleotide translocase activity. Cancer Res. 2003 Jan 15;63(2):541-6.
49. Zamzami N, Kroemer G. Apoptosis: Mitochondrial membrane permeabilization--the (w)hole story? Curr Biol. 2003 Jan 21;13(2):R71-3.
50. Waterhouse NJ, Ricci JE, Green DR. And all of a sudden it's over: Mitochondrial outer-membrane permeabilization in apoptosis. Biochimie. 2002 Feb-Mar;84(2-3):113-21.
51. Crompton M. Bax, bid and the permeabilization of the mitochondrial outer membrane in apoptosis. Curr Opin Cell Biol. 2000 Aug;12(4):414-9.
52. Benedict CA, Norris PS, Ware CF. To kill or be killed: Viral evasion of apoptosis. Nat Immunol. 2002 Nov;3(11):1013-8.
53. Hay S, Kannourakis G. A time to kill: Viral manipulation of the cell death program. J Gen Virol. 2002 Jul;83(Pt 7):1547-64.
54. Cuconati A, White E. Viral homologs of BCL-2: Role of apoptosis in the regulation of virus infection. Genes Dev. 2002 Oct 1;16(19):2465-78.
55. Henderson S, Huen D, Rowe M, Dawson C, Johnson G, Rickinson A. Epstein-barr virus-coded BHRF1 protein, a viral homologue of bcl-2, protects human B cells from programmed cell death. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8479-83.
56. Hickish T, Robertson D, Clarke P, Hill M, di Stefano F, Clarke C, et al. Ultrastructural localization of BHRF1: An epstein-barr virus gene product which has homology with bcl-2. Cancer Res. 1994 May 15;54(10):2808-11.
57. Li LY, Liu MY, Shih HM, Tsai CH, Chen JY. Human cellular protein VRK2 interacts specifically with epstein-barr virus BHRF1, a homologue of bcl-2, and enhances cell survival. J Gen Virol. 2006 Oct;87(Pt 10):2869-78.
58. Marshall WL, Yim C, Gustafson E, Graf T, Sage DR, Hanify K, et al. Epstein-barr virus encodes a novel homolog of the bcl-2 oncogene that inhibits apoptosis and associates with bax and bak. J Virol. 1999 Jun;73(6):5181-5.
59. Bellows DS, Howell M, Pearson C, Hazlewood SA, Hardwick JM. Epstein-barr virus BALF1 is a BCL-2-like antagonist of the herpesvirus antiapoptotic BCL-2 proteins. J Virol. 2002 Mar;76(5):2469-79.
60. Derfuss T, Fickenscher H, Kraft MS, Henning G, Lengenfelder D, Fleckenstein B, et al. Antiapoptotic activity of the herpesvirus saimiri-encoded bcl-2 homolog: Stabilization of mitochondria and inhibition of caspase-3-like activity. J Virol. 1998 Jul;72(7):5897-904.
61. Shimizu S, Konishi A, Kodama T, Tsujimoto Y. BH4 domain of antiapoptotic bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3100-5.
62. Perez D, White E. TNF-alpha signals apoptosis through a bid-dependent conformational change in bax that is inhibited by E1B 19K. Mol Cell. 2000 Jul;6(1):53-63.
63. Afonso CL, Neilan JG, Kutish GF, Rock DL. An african swine fever virus Bc1-2 homolog, 5-HL, suppresses apoptotic cell death. J Virol. 1996 Jul;70(7):4858-63.
64. Brun A, Rivas C, Esteban M, Escribano JM, Alonso C. African swine fever virus gene A179L, a viral homologue of bcl-2, protects cells from programmed cell death. Virology. 1996 Nov 1;225(1):227-30.
65. Lu YW, Chen WN. Human hepatitis B virus X protein induces apoptosis in HepG2 cells: Role of BH3 domain. Biochem Biophys Res Commun. 2005 Dec 23;338(3):1551-6.
66. Rahmani Z, Huh KW, Lasher R, Siddiqui A. Hepatitis B virus X protein colocalizes to mitochondria with a human voltage-dependent anion channel, HVDAC3, and alters its transmembrane potential. J Virol. 2000 Mar;74(6):2840-6.
67. Bernardi P. Mitochondrial transport of cations: Channels, exchangers, and permeability transition. Physiol Rev. 1999 Oct;79(4):1127-55.
68. Garlid KD, Sun X, Paucek P, Woldegiorgis G. Mitochondrial cation transport systems. Methods Enzymol. 1995;260:331-48.
69. Bernardi P, Scorrano L, Colonna R, Petronilli V, Di Lisa F. Mitochondria and cell death. mechanistic aspects and methodological issues. Eur J Biochem. 1999 Sep;264(3):687-701.
70. Colombini M, Blachly-Dyson E, Forte M. VDAC, a channel in the outer mitochondrial membrane. Ion Channels. 1996;4:169-202.
71. Forte M, Blachly-Dyson E, Colombini M. Structure and function of the yeast outer mitochondrial membrane channel, VDAC. Soc Gen Physiol Ser. 1996;51:145-54.
72. Hunter DR, Haworth RA. The Ca2+-induced membrane transition in mitochondria. I. the protective mechanisms. Arch Biochem Biophys. 1979 Jul;195(2):453-9.
73. Pebay-Peyroula E, Dahout-Gonzalez C, Kahn R, Trezeguet V, Lauquin GJ, Brandolin G. Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature. 2003 Nov 6;426(6962):39-44.
74. Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature. 2004 Jan 29;427(6973):461-5.
75. Halestrap AP. Mitochondrial permeability: Dual role for the ADP/ATP translocator? Nature. 2004 Aug 26;430(7003):1 p following 983.
76. Takada S, Shirakata Y, Kaneniwa N, Koike K. Association of hepatitis B virus X protein with mitochondria causes mitochondrial aggregation at the nuclear periphery, leading to cell death. Oncogene. 1999 Nov 25;18(50):6965-73.
77. Diao J, Khine AA, Sarangi F, Hsu E, Iorio C, Tibbles LA, et al. X protein of hepatitis B virus inhibits fas-mediated apoptosis and is associated with up-regulation of the SAPK/JNK pathway. J Biol Chem. 2001 Mar 16;276(11):8328-40.
78. Kekule AS, Lauer U, Weiss L, Luber B, Hofschneider PH. Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature. 1993 Feb 25;361(6414):742-5.
79. Su F, Schneider RJ. Hepatitis B virus HBx protein activates transcription factor NF-kappaB by acting on multiple cytoplasmic inhibitors of rel-related proteins. J Virol. 1996 Jul;70(7):4558-66.
80. Benn J, Su F, Doria M, Schneider RJ. Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-jun N-terminal mitogen-activated protein kinases. J Virol. 1996 Aug;70(8):4978-85.
81. Henkler F, Lopes AR, Jones M, Koshy R. Erk-independent partial activation of AP-1 sites by the hepatitis B virus HBx protein. J Gen Virol. 1998 Nov;79 ( Pt 11)(Pt 11):2737-42.
82. Shih WL, Kuo ML, Chuang SE, Cheng AL, Doong SL. Hepatitis B virus X protein inhibits transforming growth factor-beta -induced apoptosis through the activation of phosphatidylinositol 3-kinase pathway. J Biol Chem. 2000 Aug 18;275(33):25858-64.
83. Tanaka Y, Kanai F, Kawakami T, Tateishi K, Ijichi H, Kawabe T, et al. Interaction of the hepatitis B virus X protein (HBx) with heat shock protein 60 enhances HBx-mediated apoptosis. Biochemical and Biophysical Research Communications. 2004/5/28;318(2):461-9.
84. Machida K, Cheng KT, Lai CK, Jeng KS, Sung VM, Lai MM. Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation. J Virol. 2006 Jul;80(14):7199-207.
85. Carrere-Kremer S, Montpellier-Pala C, Cocquerel L, Wychowski C, Penin F, Dubuisson J. Subcellular localization and topology of the p7 polypeptide of hepatitis C virus. J Virol. 2002 Apr;76(8):3720-30.
86. Gonzalez ME, Carrasco L. Viroporins. FEBS Lett. 2003 Sep 18;552(1):28-34.
87. Griffin SD, Harvey R, Clarke DS, Barclay WS, Harris M, Rowlands DJ. A conserved basic loop in hepatitis C virus p7 protein is required for amantadine-sensitive ion channel activity in mammalian cells but is dispensable for localization to mitochondria. J Gen Virol. 2004 Feb;85(Pt 2):451-61.
88. Pavlovic D, Neville DC, Argaud O, Blumberg B, Dwek RA, Fischer WB, et al. The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6104-8.
89. Goldmacher VS, Bartle LM, Skaletskaya A, Dionne CA, Kedersha NL, Vater CA, et al. A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to bcl-2. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12536-41.
90. Poncet D, Larochette N, Pauleau AL, Boya P, Jalil AA, Cartron PF, et al. An anti-apoptotic viral protein that recruits bax to mitochondria. J Biol Chem. 2004 May 21;279(21):22605-14.
91. Arnoult D, Bartle LM, Skaletskaya A, Poncet D, Zamzami N, Park PU, et al. Cytomegalovirus cell death suppressor vMIA blocks bax- but not bak-mediated apoptosis by binding and sequestering bax at mitochondria. Proc Natl Acad Sci U S A. 2004 May 25;101(21):7988-93.
92. Vieira HL, Belzacq AS, Haouzi D, Bernassola F, Cohen I, Jacotot E, et al. The adenine nucleotide translocator: A target of nitric oxide, peroxynitrite, and 4-hydroxynonenal. Oncogene. 2001 Jul 19;20(32):4305-16.
93. Boya P, Morales MC, Gonzalez-Polo RA, Andreau K, Gourdier I, Perfettini JL, et al. The chemopreventive agent N-(4-hydroxyphenyl)retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the bcl-2 family. Oncogene. 2003 Sep 18;22(40):6220-30.
94. McCormick AL, Smith VL, Chow D, Mocarski ES. Disruption of mitochondrial networks by the human cytomegalovirus UL37 gene product viral mitochondrion-localized inhibitor of apoptosis. J Virol. 2003 Jan;77(1):631-41.
95. Deniaud A, Brenner C, Kroemer G. Mitochondrial membrane permeabilization by HIV-1 vpr. Mitochondrion. 2004 Jul;4(2-3):223-33.
96. Jacotot E, Ravagnan L, Loeffler M, Ferri KF, Vieira HL, Zamzami N, et al. The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore. J Exp Med. 2000 Jan 3;191(1):33-46.
97. Azuma A, Matsuo A, Suzuki T, Kurosawa T, Zhang X, Aida Y. Human immunodeficiency virus type 1 vpr induces cell cycle arrest at the G(1) phase and apoptosis via disruption of mitochondrial function in rodent cells. Microbes Infect. 2006 Mar;8(3):670-9.
98. Macho A, Calzado MA, Jimenez-Reina L, Ceballos E, Leon J, Munoz E. Susceptibility of HIV-1-TAT transfected cells to undergo apoptosis. biochemical mechanisms. Oncogene. 1999 Dec 9;18(52):7543-51.
99. Nudson WA, Rovnak J, Buechner M, Quackenbush SL. Walleye dermal sarcoma virus orf C is targeted to the mitochondria. J Gen Virol. 2003 Feb;84(Pt 2):375-81.
100. Macen JL, Graham KA, Lee SF, Schreiber M, Boshkov LK, McFadden G. Expression of the myxoma virus tumor necrosis factor receptor homologue and M11L genes is required to prevent virus-induced apoptosis in infected rabbit T lymphocytes. Virology. 1996 Apr 1;218(1):232-7.
101. Everett H, Barry M, Lee SF, Sun X, Graham K, Stone J, et al. M11L: A novel mitochondria-localized protein of myxoma virus that blocks apoptosis of infected leukocytes. J Exp Med. 2000 May 1;191(9):1487-98.
102. Everett H, Barry M, Sun X, Lee SF, Frantz C, Berthiaume LG, et al. The myxoma poxvirus protein, M11L, prevents apoptosis by direct interaction with the mitochondrial permeability transition pore. J Exp Med. 2002 Nov 4;196(9):1127-39.
103. Brown J, Higo H, McKalip A, Herman B. Human papillomavirus (HPV) 16 E6 sensitizes cells to atractyloside-induced apoptosis: Role of p53, ICE-like proteases and the mitochondrial permeability transition. J Cell Biochem. 1997 Aug 1;66(2):245-55.
104. Jackson S, Harwood C, Thomas M, Banks L, Storey A. Role of bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev. 2000 Dec 1;14(23):3065-73.
105. Thomas M, Banks L. Human papillomavirus (HPV) E6 interactions with bak are conserved amongst E6 proteins from high and low risk HPV types. J Gen Virol. 1999 Jun;80 ( Pt 6)(Pt 6):1513-7.
106. Leverrier S, Bergamaschi D, Ghali L, Ola A, Warnes G, Akgul B, et al. Role of HPV E6 proteins in preventing UVB-induced release of pro-apoptotic factors from the mitochondria. Apoptosis. 2007 Mar;12(3):549-60.
107. Wasilenko ST, Stewart TL, Meyers AF, Barry M. Vaccinia virus encodes a previously uncharacterized mitochondrial-associated inhibitor of apoptosis. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14345-50.
108. Wasilenko ST, Banadyga L, Bond D, Barry M. The vaccinia virus F1L protein interacts with the proapoptotic protein bak and inhibits bak activation. J Virol. 2005 Nov;79(22):14031-43.
109. Taylor JM, Quilty D, Banadyga L, Barry M. The vaccinia virus protein F1L interacts with bim and inhibits activation of the pro-apoptotic protein bax. J Biol Chem. 2006 Dec 22;281(51):39728-39.
110. Stewart TL, Wasilenko ST, Barry M. Vaccinia virus F1L protein is a tail-anchored protein that functions at the mitochondria to inhibit apoptosis. J Virol. 2005 Jan;79(2):1084-98.
111. Wasilenko ST, Meyers AF, Vander Helm K, Barry M. Vaccinia virus infection disarms the mitochondrion-mediated pathway of the apoptotic cascade by modulating the permeability transition pore. J Virol. 2001 Dec;75(23):11437-48.
112. Chen W, Calvo PA, Malide D, Gibbs J, Schubert U, Bacik I, et al. A novel influenza A virus mitochondrial protein that induces cell death. Nat Med. 2001 Dec;7(12):1306-12.
113. Bruns K, Studtrucker N, Sharma A, Fossen T, Mitzner D, Eissmann A, et al. Structural characterization and oligomerization of PB1-F2, a proapoptotic influenza A virus protein. J Biol Chem. 2007 Jan 5;282(1):353-63.
114. Gibbs JS, Malide D, Hornung F, Bennink JR, Yewdell JW. The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function. J Virol. 2003 Jul;77(13):7214-24.
115. Zamarin D, Garcia-Sastre A, Xiao X, Wang R, Palese P. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog. 2005 Sep;1(1):e4.
116. Ciminale V, Zotti L, D'Agostino DM, Ferro T, Casareto L, Franchini G, et al. Mitochondrial targeting of the p13II protein coded by the x-II ORF of human T-cell leukemia/lymphotropic virus type I (HTLV-I). Oncogene. 1999 Aug 5;18(31):4505-14.
117. D'Agostino DM, Silic-Benussi M, Hiraragi H, Lairmore MD, Ciminale V. The human T-cell leukemia virus type 1 p13II protein: Effects on mitochondrial function and cell growth. Cell Death Differ. 2005 Aug;12 Suppl 1:905-15.
118. D'Agostino DM, Ranzato L, Arrigoni G, Cavallari I, Belleudi F, Torrisi MR, et al. Mitochondrial alterations induced by the p13II protein of human T-cell leukemia virus type 1. critical role of arginine residues. J Biol Chem. 2002 Sep 13;277(37):34424-33.
119. D'Agostino DM, Zotti L, Ferro T, Franchini G, Chieco-Bianchi L, Ciminale V. The p13II protein of HTLV type 1: Comparison with mitochondrial proteins coded by other human viruses. AIDS Res Hum Retroviruses. 2000 Nov 1;16(16):1765-70.
120. Silic-Benussi M, Cavallari I, Zorzan T, Rossi E, Hiraragi H, Rosato A, et al. Suppression of tumor growth and cell proliferation by p13II, a mitochondrial protein of human T cell leukemia virus type 1. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6629-34.
121. Rasola A, Gramaglia D, Boccaccio C, Comoglio PM. Apoptosis enhancement by the HIV-1 nef protein. J Immunol. 2001 Jan 1;166(1):81-8.
122. Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 1999 Aug 1;13(15):1899-911.
123. Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998 Aug 28;281(5381):1309-12.
124. Shimizu S, Eguchi Y, Kamiike W, Funahashi Y, Mignon A, Lacronique V, et al. Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1455-9.
125. Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC. HIV-1 nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature. 2001 Apr 12;410(6830):834-8.
126. Livne A, Shtrichman R, Kleinberger T. Caspase activation by adenovirus e4orf4 protein is cell line specific and is mediated by the death receptor pathway. J Virol. 2001 Jan;75(2):789-98.
127. Ray RB, Meyer K, Steele R, Shrivastava A, Aggarwal BB, Ray R. Inhibition of tumor necrosis factor (TNF-alpha)-mediated apoptosis by hepatitis C virus core protein. J Biol Chem. 1998 Jan 23;273(4):2256-9.
128. Ruggieri A, Harada T, Matsuura Y, Miyamura T. Sensitization to fas-mediated apoptosis by hepatitis C virus core protein. Virology. 1997 Mar 3;229(1):68-76.
129. Matthews DA, Russell WC. Adenovirus core protein V interacts with p32--a protein which is associated with both the mitochondria and the nucleus. J Gen Virol. 1998 Jul;79 ( Pt 7)(Pt 7):1677-85.
130. Cen S, Khorchid A, Javanbakht H, Gabor J, Stello T, Shiba K, et al. Incorporation of lysyl-tRNA synthetase into human immunodeficiency virus type 1. J Virol. 2001 Jun;75(11):5043-8.
131. Tolkunova E, Park H, Xia J, King MP, Davidson E. The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual alternative splicing of the primary transcript. J Biol Chem. 2000 Nov 10;275(45):35063-9.
132. Kaminska M, Shalak V, Francin M, Mirande M. Viral hijacking of mitochondrial lysyl-tRNA synthetase. J Virol. 2007 Jan;81(1):68-73.
133. Stark LA, Hay RT. Human immunodeficiency virus type 1 (HIV-1) viral protein R (vpr) interacts with lys-tRNA synthetase: Implications for priming of HIV-1 reverse transcription. J Virol. 1998 Apr;72(4):3037-44.
134. Kim S, Kim HY, Lee S, Kim SW, Sohn S, Kim K, et al. Hepatitis B virus x protein induces perinuclear mitochondrial clustering in microtubule- and dynein-dependent manners. J Virol. 2007 Feb;81(4):1714-26.
135. Nomura-Takigawa Y, Nagano-Fujii M, Deng L, Kitazawa S, Ishido S, Sada K, et al. Non-structural protein 4A of hepatitis C virus accumulates on mitochondria and renders the cells prone to undergoing mitochondria-mediated apoptosis. J Gen Virol. 2006 Jul;87(Pt 7):1935-45.
136. Rojo G, Chamorro M, Salas ML, Vinuela E, Cuezva JM, Salas J. Migration of mitochondria to viral assembly sites in african swine fever virus-infected cells. J Virol. 1998 Sep;72(9):7583-8.
137. Kelly DC. Frog virus 3 replication: Electron microscope observations on the sequence of infection in chick embryo fibroblasts. J Gen Virol. 1975 Jan;26(1):71-86.
138. Radovanovic J, Todorovic V, Boricic I, Jankovic-Hladni M, Korac A. Comparative ultrastructural studies on mitochondrial pathology in the liver of AIDS patients: Clusters of mitochondria, protuberances, "minimitochondria," vacuoles, and virus-like particles. Ultrastruct Pathol. 1999 Jan-Feb;23(1):19-24.
139. Hara Y, Hino K, Okuda M, Furutani T, Hidaka I, Yamaguchi Y, et al. Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species. J Gastroenterol. 2006 Mar;41(3):257-68.
140. Tollefson AE, Ryerse JS, Scaria A, Hermiston TW, Wold WS. The E3-11.6-kDa adenovirus death protein (ADP) is required for efficient cell death: Characterization of cells infected with adp mutants. Virology. 1996 Jun 1;220(1):152-62.
141. Monne M, Robinson AJ, Boes C, Harbour ME, Fearnley IM, Kunji ER. THE MIMIVIRUS GENOME ENCODES A MITOCHONDRIAL CARRIER THAT TRANSPORTS dATP AND dTTP. J Virol. 2007 Jan 17.
142. Saffran HA, Pare JM, Corcoran JA, Weller SK, Smiley JR. Herpes simplex virus eliminates host mitochondrial DNA. EMBO Rep. 2007 Feb;8(2):188-93.
143. Hardwicke MA, Sandri-Goldin RM. The herpes simplex virus regulatory protein ICP27 contributes to the decrease in cellular mRNA levels during infection. J Virol. 1994 Aug;68(8):4797-810.
144. Spencer CA, Dahmus ME, Rice SA. Repression of host RNA polymerase II transcription by herpes simplex virus type 1. J Virol. 1997 Mar;71(3):2031-40.
145. Radsak KD, Freise HW. Stimulation of mitochondrial DNA synthesis in HeLa cells by herpes simplex virus. Life Sci II. 1972 Jul 22;11(14):717-24.
146. Radsak K. DNA synthesis in isolated nuclei and mitochondria from HeLa cells infected by herpes simplex virus. Zentralbl Bakteriol [Orig A]. 1974;227(1-4):345-7.
147. Radsak K, Albring M. Stimulation of mitochondrial DNA synthesis as an early function of herpes simplex virus. FEBS Lett. 1974 Aug 25;44(2):136-40.
148. Radsak K, Albring M. Herpes simplex virus-induced enhancement of mitochondrial DNA synthesis in the absence of virus replication. J Gen Virol. 1974 Dec;25(3):457-63.
149. Katze MG, He Y, Gale M,Jr. Viruses and interferon: A fight for supremacy. Nat Rev Immunol. 2002 Sep;2(9):675-87.
150. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004 Jul;4(7):499-511.
151. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3. Nature. 2001 Oct 18;413(6857):732-8.
152. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004 Jul;5(7):730-7.
153. Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, Goodbourn S, et al. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17264-9.
154. Maniatis T, Falvo JV, Kim TH, Kim TK, Lin CH, Parekh BS, et al. Structure and function of the interferon-beta enhanceosome. Cold Spring Harb Symp Quant Biol. 1998;63:609-20.
155. Seth RB, Sun L, Ea CK, Chen ZJ. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005 Sep 9;122(5):669-82.
156. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005 Sep 16;19(6):727-40.
157. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol. 2005 Oct;6(10):981-8.
158. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005 Oct 20;437(7062):1167-72.
159. Sun Q, Sun L, Liu HH, Chen X, Seth RB, Forman J, et al. The specific and essential role of MAVS in antiviral innate immune responses. Immunity. 2006 May;24(5):633-42.
160. Breiman A, Grandvaux N, Lin R, Ottone C, Akira S, Yoneyama M, et al. Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKepsilon. J Virol. 2005 Apr;79(7):3969-78.
161. Foy E, Li K, Sumpter R,Jr, Loo YM, Johnson CL, Wang C, et al. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2986-91.
162. Foy E, Li K, Wang C, Sumpter R,Jr, Ikeda M, Lemon SM, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003 May 16;300(5622):1145-8.
163. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17717-22.
164. Beames B, Chavez D, Lanford RE. GB virus B as a model for hepatitis C virus. ILAR J. 2001;42(2):152-60.
165. Chen Z, Benureau Y, Rijnbrand R, Yi J, Wang T, Warter L, et al. GB virus B disrupts RIG-I signaling by NS3/4A-mediated cleavage of the adaptor protein MAVS. J Virol. 2007 Jan;81(2):964-76.
166. Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, et al. Inhibition of bax channel-forming activity by bcl-2. Science. 1997 Jul 18;277(5324):370-2.
167. Schimmer AD, Hedley DW, Pham NA, Chow S, Minden MD. BAD induces apoptosis in cells over-expressing bcl-2 or bcl-xL without loss of mitochondrial membrane potential. Leuk Lymphoma. 2001 Jul;42(3):429-43.
168. Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell. 1997 Nov 28;91(5):627-37.
169. Schmitt E, Paquet C, Beauchemin M, Bertrand R. Bcl-xES, a BH4- and BH2-containing antiapoptotic protein, delays bax oligomer formation and binds apaf-1, blocking procaspase-9 activation. Oncogene. 2004 May 13;23(22):3915-31.
170. Kroemer G, Reed JC. Mitochondrial control of cell death. Nat Med. 2000 May;6(5):513-9.
171. Antonsson B. Mitochondria and the bcl-2 family proteins in apoptosis signaling pathways. Mol Cell Biochem. 2004 Jan-Feb;256-257(1-2):141-55.
172. Akhtar RS, Geng Y, Klocke BJ, Latham CB, Villunger A, Michalak EM, et al. BH3-only proapoptotic bcl-2 family members noxa and puma mediate neural precursor cell death. J Neurosci. 2006 Jul 5;26(27):7257-64.
173. Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ, et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science. 2003 Nov 7;302(5647):1036-8.
174. Hu CA, Donald SP, Yu J, Lin WW, Liu Z, Steel G, et al. Overexpression of proline oxidase induces proline-dependent and mitochondria-mediated apoptosis. Mol Cell Biochem. 2007 Jan;295(1-2):85-92.
175. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997 Nov 14;91(4):479-89.
176. Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M, et al. Two distinct pathways leading to nuclear apoptosis. J Exp Med. 2000 Aug 21;192(4):571-80.
177. Er E, Oliver L, Cartron PF, Juin P, Manon S, Vallette FM. Mitochondria as the target of the pro-apoptotic protein bax. Biochim Biophys Acta. 2006 Sep-Oct;1757(9-10):1301-11.
178. Xie Q, Lin T, Zhang Y, Zheng J, Bonanno JA. Molecular cloning and characterization of a human AIF-like gene with ability to induce apoptosis. J Biol Chem. 2005 May 20;280(20):19673-81.
179. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999 Feb 4;397(6718):441-6.
180. Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in parkinson's disease. Hum Mol Genet. 2005 Aug 1;14(15):2099-111.
181. Jones JM, Datta P, Srinivasula SM, Ji W, Gupta S, Zhang Z, et al. Loss of omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature. 2003 Oct 16;425(6959):721-7.
182. Rostovtseva TK, Tan W, Colombini M. On the role of VDAC in apoptosis: Fact and fiction. J Bioenerg Biomembr. 2005 Jun;37(3):129-42.
183. Belzacq AS, Vieira HL, Kroemer G, Brenner C. The adenine nucleotide translocator in apoptosis. Biochimie. 2002 Feb-Mar;84(2-3):167-76.
184. Halestrap AP. Calcium, mitochondria and reperfusion injury: A pore way to die. Biochem Soc Trans. 2006 Apr;34(Pt 2):232-7.
185. Tsujimoto Y, Nakagawa T, Shimizu S. Mitochondrial membrane permeability transition and cell death. Biochim Biophys Acta. 2006 Sep-Oct;1757(9-10):1297-300.

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.