Student
Perspectives on Contemporary Virology
- Volume 1, 2007
Mitochondria
and Viruses
(unreviewed)
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
Table
of Contents
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.
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 memeberane, 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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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.