Viruses as Modulators of Mitochondrial Functions

Anand, Sanjeev K.; Tikoo, Suresh K.

doi:https://doi.org/10.1155/2013/738794

Advances in Virology

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Review Article | Open Access

Volume 2013 | Article ID 738794 | https://doi.org/10.1155/2013/738794

Viruses as Modulators of Mitochondrial Functions

Sanjeev K. Anand^1,2and Suresh K. Tikoo^1,2,3

Academic Editor: Michael Bukrinsky

Received26 Jun 2013

Accepted30 Aug 2013

Published24 Oct 2013

Abstract

Mitochondria are multifunctional organelles with diverse roles including energy production and distribution, apoptosis, eliciting host immune response, and causing diseases and aging. Mitochondria-mediated immune responses might be an evolutionary adaptation by which mitochondria might have prevented the entry of invading microorganisms thus establishing them as an integral part of the cell. This makes them a target for all the invading pathogens including viruses. Viruses either induce or inhibit various mitochondrial processes in a highly specific manner so that they can replicate and produce progeny. Some viruses encode the Bcl2 homologues to counter the proapoptotic functions of the cellular and mitochondrial proteins. Others modulate the permeability transition pore and either prevent or induce the release of the apoptotic proteins from the mitochondria. Viruses like Herpes simplex virus 1 deplete the host mitochondrial DNA and some, like human immunodeficiency virus, hijack the host mitochondrial proteins to function fully inside the host cell. All these processes involve the participation of cellular proteins, mitochondrial proteins, and virus specific proteins. This review will summarize the strategies employed by viruses to utilize cellular mitochondria for successful multiplication and production of progeny virus.

1. Introduction

1.1. Mitochondria

Mitochondria are cellular organelles found in the cytoplasm of almost all eukaryotic cells. One of their important functions is to produce and provide energy to the cell in the form of ATP, which help in proper maintenance of the cellular processes, thus making them indispensable for the cell. Besides acting as a powerhouse for the cell, they act as a common platform for the execution of a variety of cellular functions in normal or microorganism infected cells. Mitochondria have been implicated in aging [1, 2], apoptosis [3–7], the regulation of cell metabolism [4, 8], cell-cycle control [9–11], development of the cell [12–14], antiviral responses [15], signal transduction [16], and diseases [17–20].

Although all mitochondria have the same architecture, they vary greatly in shape and size. The mitochondria are composed of outer mitochondrial membrane, inner mitochondrial membrane, intermembrane space (space between outer and inner membrane), and matrix (space within inner mitochondrial membrane). The outer membrane is a smooth phospholipid bilayer, with different types of proteins imbedded in it [21]. The most important of them are the porins, which freely allow the transport (export and import) of the molecules (proteins, ions, nutrients, and ATP) less than 10 kDa across the membranes. The outer membrane surrounds the inner membrane creating an intermembrane space that contains molecules such as Cyt-C, SMAC/Diablo, and endonuclease G. It also acts as a buffer zone between the outer membrane and the inner membrane of mitochondria. The inner membrane is highly convoluted into structures called cristae, which increases the surface area of the membrane and are the seats of respiratory complexes. The inner membrane of mitochondria allows the free transport of oxygen and carbon dioxide. The movement of water through membranes is suggested to be controlled by aquaporins channel protein [22, 23] though a report suggested otherwise [24]. 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.

Mitochondria contain a single 16 kb circular DNA genome, which codes for 13 proteins (mostly subunits of respiratory chains I, II, IV, and V), 22 mitochondrial tRNAs and 2 rRNAs [25, 26]. The mitochondrial genome is not enveloped (like nuclear envelop), contains few introns, and does not follow universal genetic code [27]. Although the majority of the mitochondrial proteins are encoded by nuclear DNA and imported into the mitochondria (reviewed by [21, 28–31]), mitochondria synthesize few proteins that are essential for their respiratory function [1, 27].

Proteins destined to mitochondria have either internally localized [28] or amino terminal localized [21] presequences known as mitochondria/matrix localization signals (MLS), which can be 10–80 amino acid long with predominantly positively charged amino acids. The combination of these presequences with adjacent regions determines the localization of a protein in respective mitochondrial compartments. The outer mitochondrial membrane contains two major translocators, namely, (a) the translocase of outer membrane (TOM) 40, which functions as an entry gate for most mitochondrial proteins with MLS and (b) sorting and assembly machinery (SAM) or translocase of β-barrel (TOB) protein, which is a specialized insertion machinery for beta-barrel membrane proteins [32]. Once proteins pass through the outer membrane, they are recruited by presequence translocase-associated motor (PAM) to the translocase of the inner mitochondrial membrane (TIM) 23 complexes, which mediates the import of proteins to the matrix. Finally, the presequences are cleaved in matrix and proteins are modified to their tertiary structure, and rendered functional [30].

1.2. Viruses

Viruses are acellular obligate intracellular microorganisms that infect the living cells/organisms and are the only exception to cell theory proposed by Schleiden and Schwann in 1838/1839 [33]. The viruses have an outer protein capsid and a nucleic acid core. Usually, the viral nucleic acids can be either DNA (double or single stranded) or RNA (+ or − sense single stranded or double stranded RNA). Some of the viruses are covered with an envelope embedded 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 was studied in detail. In order to survive and replicate in the cell, viruses need to take control of the various cellular organelles involved in defense and immune processes. They also require energy to replicate and escape from the cell. Once inside the host cell, they modulate various cellular signal pathways and organelles, including mitochondria, and use them for their own survival and replication. This review summarizes the functions of mitochondria and how viruses modulate them (Figure 1).

Figure 1

Schematic diagram of cell showing mitochondria, nucleus endoplasmic reticulum (ER) and cell membrane. iCa²⁺: intracellular calcium, FADD: Fas-associated protein with death domain, TRADD: tumor necrosis factor receptor type 1-associated death domain protein, PTP: permeability transition pore, VDAC: voltage-dependent anion channel, IP₃R: inositol 1,4,5-trisphosphate receptor, RyR: ryanodine receptor, MAVS: mitochondrial antiviral signaling, I, II, III, and IV are complex I to IV of electron transport chain. : Superoxide radical, Bad, Bcl-2-associated death promoter, ROS: reactive oxygen species, IFN: interferon, HCMV: human cytomegalovirus, HIV: human immunodeficiency virus, HSV: herpes simplex virus, HBV: hepatitis B virus, HTLV: human T-lymphotropic virus, IA: influenza A virus, WDSV: Walleye dermal sarcoma virus, HCV: hepatitis C virus, HAdV: human adenovirus-5, EBV: Epstein-Barr virus, and EMCV: encephalomyocarditis virus.

2. Viruses Regulate Ca²⁺ Homeostasis in Host Cells

2.1. Ca²⁺ Homeostasis

Ca²⁺ is one of the most abundant and versatile elements in the cell and acts as a second messenger to regulate many cellular processes [34]. Earlier, outer membrane of mitochondria was thought to be permeable to Ca²⁺, but recent studies suggest that the outer membrane contains voltage-dependent anion channels (VDAC) having Ca²⁺ binding domains, which regulate the entry of Ca²⁺ into the mitochondrial intermembrane space [35–37]. The influx of Ca²⁺ through the inner membrane is regulated by the mitochondrial Ca²⁺ uniporter (MCU), which is a highly selective Ca²⁺ channel that regulates the Ca²⁺ uptake based on mitochondrial membrane potential (MMP). The net movement of charge due to Ca²⁺ uptake is directly proportional to the decrease of MMP [38]. A second mechanism that helps in Ca²⁺ movement across the mitochondria membrane is called “rapid mode” uptake mechanism (RaM) [39]. In this process, Ca²⁺ transports across the mitochondrial membrane by exchange with Na⁺, which in turn depends upon its exchange with H⁺ ion and thus MMP. This ion exchange across the mitochondrial membrane decreases MMP and is dependent on electron transport chain (ETC) for its maintenance. A third mechanism involves IP₃R, a Ca²⁺ channel in endoplasmic reticulum. IP₃R is connected to mitochondrial VDAC through a glucose regulating protein 75 (GRP75). This junction regulates/facilitates Ca²⁺ exchange from IP₃R to VDAC [40].

Ca²⁺ efflux mechanism is regulated by the permeability transition pore (PTP). The PTP is assembled in the mitochondrial inner and outer membranes [41, 42], with Ca²⁺ binding sites on the matrix side of the inner membrane. The PTP regulates the mitochondrial Ca²⁺ release by a highly regulated “Flickering” mechanism that controls the opening and closing of the pore [43]. RaM works in sync with ryanodine receptor (RyR) isoform 1, which is another very important calcium release channel [44]. Both RyR and RaM regulate the phenomenon of excitation-metabolism coupling in which cytosolic Ca²⁺ induced contraction is matched by mitochondrial Ca²⁺ stimulation of ox-phos [45]. However, mitochondrial Ca²⁺ overload can result in prolonged opening of the pore leading to pathology [46]. Although Ca²⁺ is involved in the activation of many cellular processes including stimulation of the ATP synthase [47, 48], allosteric activation of Krebs cycle enzymes [49, 50], and the adenine nucleotide translocase (ANT) [51], the primary role of mitochondrial Ca²⁺ is in the stimulation of ox-phos [52–54]. Thus, the elevated mitochondrial Ca²⁺ results in up regulation of the entire ox-phos machinery, which then results in faster respiratory chain activity and higher ATP output, which can then meet the cellular ATP demand. Ca²⁺ also upregulates other mitochondrial functions including activation of N-acetylglutamine synthetase to generate N-acetylglutamine [55], potent allosteric activation of carbamoyl-phosphate synthetase, and the urea cycle [56]. Thus, any perturbation in mitochondrial or cytosolic Ca²⁺ homeostasis has profound implications for cell function. Moreover, mitochondrial Ca²⁺, particularly at high concentrations experienced in pathology appears to have several negative effects on mitochondrial functions [57].

2.2. Regulation by Viruses

A number of viruses alter the Ca²⁺regulatory activity of the cell for their survival. Herpes simplex type (HSV) 1 virus causes a gradual decline (65%) in mitochondrial Ca²⁺ uptake at 12 hrs lytic cycle [58], which helps in virus replication. Although mitochondrial Ca²⁺ uptake keeps fluctuating throughout the course of a measles virus infection of cells, the total amount of cellular Ca²⁺ remains the same [58] indicating the tight control that the virus exerts over the cellular processes during its life cycle.

The core protein of hepatitis C virus (HCV) targets mitochondria and increases Ca²⁺ [59, 60]. The NS5A protein of HCV causes alterations in Ca²⁺ homeostasis [61–63]. Both of these proteins may be responsible for the pathogenesis of liver disorders associated with HCV infection. Even in the cells coinfected with HCV and human immunodeficiency virus (HIV), these viruses enhance the MCU activity causing cellular stress and apoptosis [59, 64]. The p7 protein of HCV forms porin-like structures [65] and causes Ca²⁺ influx to cytoplasm from storage organelles [66]. These HCV proteins disturb the Ca²⁺ homeostasis at different stages of the infection and thus help to enhance the survival of the cell. Interestingly, interaction of protein X of hepatitis B virus (HBV) with VDAC causes the release of Ca²⁺ from storage organelles mitochondria/endoplasmic reticulum (ER)/golgi into the cytoplasmic compartment, which appears to help virus replication [67, 68].

The Nef protein of HIV interacts with IP₃R [69] and induces an increase in cytosolic Ca²⁺ through promotion on T cell receptor-independent activation of the NFAT pathway [70]. Activated NFAT, in turn, causes the low-amplitude intracellular Ca²⁺ oscillation, promoting the viral gene transcription and replication [71].

Ca²⁺ is an important factor for different stages of rotavirus lifecycle and for stability to rotavirus virion [72]. The NSP4 protein of rotavirus increases the cytosolic Ca²⁺ concentration by activation of phospholipase C (PLC) and the resultant ER Ca²⁺ depletion through IP₃R [73, 74]. This alteration in Ca²⁺ homeostasis has been attributed to an increase in the permeability of cell membrane [75]. A decrease in cellular Ca²⁺ concentrations toward the end of the life cycle has been reported to enable rotavirus release from the cell [76].

The 2BC protein of poliovirus increases the intracellular Ca²⁺ concentrations in the cells 4 hrs. After infection, which is necessary for viral gene expression [77, 78]. Toward the end of the virus life cycle, the release of Ca²⁺ from the lumen of ER through IP₃R and RyR channels causes accumulation of Ca²⁺ in mitochondria through uniporter and VDAC resulting in mitochondrial dysfunction and apoptosis [79]. On the contrary, the 2B protein of Coxsackie virus decreases the membrane permeability by decreasing Ca²⁺ concentrations in infected cells [80, 81] due to its porin-like activity that results in Ca²⁺ efflux from the organelles. Reduced protein trafficking and low Ca²⁺ concentration in golgi and ER favor the formation of viral replication complexes, downregulate host antiviral immune response, and inhibit apoptosis [82, 83].

Enteroviruses orchestrate the apoptotic process during their life cycle to enhance its entry, survival, and release. The perturbation in cytoplasmic Ca²⁺ homeostasis at 2–4 hrs. postinfection coincides with the inhibition of the apoptotic response that can be attributed to decrease in cytotoxic levels of Ca²⁺ in the cell and the mitochondria. This also provides the virus with optimum conditions for the replication and protein synthesis. Finally, a decrease in mitochondrial and other storage organelles (ER and golgi) Ca²⁺ levels causes an increase in cytosolic Ca²⁺ concentration, leading to the formation of vesicles and cell death, thus assisting in virus release [81, 84, 85].

The pUL37 × 1 protein of human cytomegalovirus (HCMV) localizes to mitochondria [86] and causes the trafficking of Ca²⁺ from the ER to mitochondria at 4–6 hrs. After infection [87]. Active Ca²⁺ uptake by mitochondrion induces the production of ATP and other Ca²⁺ dependent enzymes accelerating virus replication, and a decrease in Ca²⁺ levels in the ER has antiapoptotic effects [88].

The 6.7K protein encoded by E3 region of HAdV-2 localizes to ER and helps maintain ER Ca²⁺ homeostasis in transfected cells, thus inhibiting apoptosis [89].

3. Viruses Cause Oxidative Stress in Host Cells

3.1. Electron Transport Chain

The mitochondrial respiratory chain is the main and most significant source of reactive oxygen species (RO) in the cell. Superoxide () is the primary ROS produced by mitochondria. In the normal state, there is little or no leakage of electrons between the complexes of the electron transport chain (ETC). However, during stress conditions, a small fraction of electrons leave complex III and reach complex IV [90]. This premature electron leakage to oxygen results in the formation of two types of superoxides, namely, , in its anionic form, and in its protonated form.

Leakage of electrons takes place mainly from Q_O sites of complex III, which are situated immediately next to the intermembrane space resulting in the release of superoxides in either the matrix or the innermembrane space of the mitochondria [91–94]. About 25–75% of the total electron leak through Complex III could account for the net extramitochondrial superoxide release [95–97]. Thus, the main source of in mitochondria is the ubisemiquinone radical intermediate (QH^•) formed during the Q cycle at the Q_O site of complex III [98–100]. Complex I is also a source of ROS, but the mechanism of ROS generation is less clear. Recent reports suggest that glutathionylation [101] or PKA mediated phosphorylation [101–103] of complex I can elevate ROS generation. Backward flow of electron from complex I to complex II can also result in the production of ROS [99].

A variety of cellular defense mechanisms maintain the steady state concentration of these oxidants at nontoxic levels. This delicate balance between ROS generation and metabolism may be disrupted by various xenobiotics including viral proteins. The main reason for generation of ROS in virus-infected cells is to limit the virus multiplication. However, ROS also acts as a signal for various cellular pathways, and the virus utilizes the chaos generated inside the cell for its replication.

3.2. Viruses Induce Reactive Oxygen Species

A number of viruses cause oxidative stress to the host cells, which directly or indirectly helps them to survive. Human-Adenovirus- (HAdV-) 5 has been reported to induce the rupture of endosomal membrane upon infection resulting in the release of lysosomal cathepsins, which prompt the production of ROS. Cathepsins also induce the disruption of mitochondrial membrane leading to the release of ROS from mitochondria thus causing the oxidative stress [104].

The core protein of HCV causes oxidative stress in the cell and alters apoptotic pathways [64, 105–107]. The E1, E2, NS3, and core protein of HCV are potent ROS inducers and can cause host DNA damage independently [107, 108] or mediated by nitric oxide (NO) thus aiding in virus replication.

The ROS is generated during HIV infection [64, 109–111]. H₂O₂, an ROS generated during HIV infection strongly induces HIV long terminal repeat (LTR) via NF-kappa B activation. Impaired LTR activity ablates the LTR activation in response to ROS thus aiding in virus replication [112]. HIV also causes extensive cellular damage due to increased ROS production and decreased cytosolic antioxidant production [113]. Coinfection of HIV and HCV causes the hepatic fibrosis, the progression of which is regulated through the generation of ROS in an NF-κB dependent manner [113].

Epstein-Barr virus (EBV) causes increased oxidative stress in the host cells within 48 hrs. During the lytic cycle indicating the role of ROS in virus release [114]. Oxidative stress activates the EBV early gene BZLF-1, which causes the reactivation of EBV lytic cycle [114]. This has been proposed to play an important role in the pathogenesis of EBV-associated diseases including malignant transformations [115, 116].

Interestingly, HBV causes both an increase and a decrease in oxidative stress to enhance its survival in the host cells [117, 118]. HBV induces strong activation of Nrf2/ARE-regulated genes in vitro and in vivo through the activation of c-Raf and MEK by HBV protein X thus protecting the cells from HBV induced oxidative stress and promoting establishment of the infection [119]. The protein X of HBV also induces the ROS mediated upregulation of Forkhead box class O4 (Foxo4), enhancing resistance to oxidative stress-induced cell death [120]. However, reports also suggest that upon exposure to oxidative stress, HBV protein X accelerates the loss of Mcl-1 protein via caspase-3 cascade thus inducing pro apoptotic effects [118]. Coinfection of HCV also causes the genotoxic effects in peripheral blood lymphocytes due to increased oxidative damage and decreased MMP [121]. It is possible that contradictory functions of protein X of HBV cold occur at different stages of virus replication.

Encephalomyocarditis virus (EMCV) causes oxidative stress in the cells during infection damaging the neurons, which is an important process in the pathogenesis of EMCV infection [122].

4. Viruses Regulate Mitochondrial Membrane Potential in Host Cells

4.1. Mitochondrial Membrane Potential

Membrane potential (MP) is the difference in voltage or electrical potential between the interior and the exterior of a membrane. The membrane potential is generated either by electrical force (mutual attraction or repulsion between both positive or negative) and/or by diffusion of particles from high to low concentrations. The mitochondrial membrane potential (MMP) is an MP ( 180 mV) across the inner membrane of mitochondria, which provides energy for the synthesis of ATP. Movement of protons from complex I to V of electron transport chain (ETC) located in the inner mitochondrial membrane creates an electric potential across the inner membrane, which is important for proper maintenance of ETC and ATP production. Reported MMP values for mitochondria (in vivo) differ from species to species and from one organ to another depending upon the mitochondria function, protein composition, and the amount of oxidative phosphorylation activity required in that part of the body [43].

The voltage dependent anionic channels (VDACs) also known as mitochondrial porins form channels in the outer mitochondrial membranes and act as primary pathway for the movement of metabolites across the outer membrane [37, 96, 123–125]. In addition, a number of factors including oxidative stress, calcium overload, and ATP depletion induce the formation of nonspecific mitochondrial permeability transition pores (MPTP) in the inner mitochondrial membrane, which is also responsible for the maintenance of MMP [36, 37, 126]. The outer membrane VDACs, inner membrane adenine nucleotide translocase (ANT) [127], and cyclophilin D (CyP-D) in matrix are the structural elements of the mitochondrial permeability transition pore (MPTP).

When open, MPTP increases the permeability of the inner mitochondrial membrane to ions and solutes up to 1.5 kDa, which causes dissipation of the MMP and diffusion of solutes down their concentration gradients, by a process known as the permeability transition [128, 129]. The MPTP opening is followed by osmotic water flux, passive swelling, outer membrane rupture, and release of proapoptotic factors leading to the cell death [42, 130]. Because of the consequent depletion of ATP and Ca²⁺ deregulation, opening of the MPTP had been proposed to be a key element in determining the fate of the cell before a role for mitochondria in apoptosis was proposed [129].

The MMP can be altered by a variety of stimuli including sudden burst of ROS [43, 107], Ca²⁺ overload in the mitochondria or the cell [48, 57, 131], and/or by proteins of invading viruses [109, 132, 133]. In general, an increase or decrease in MMP is related to the induction or prevention of apoptosis, respectively. Prevention of apoptosis during early stages of virus infection is a usual strategy employed by viruses to prevent host immune response and promote their replication. On the contrary, induction of apoptosis during later stages of virus infection is a strategy used by viruses to release the progeny virions for dissemination to the surrounding cells.

4.2. Regulation by Viruses

Many viral proteins alter mitochondrial ion permeability and/or membrane potential for their survival in the cell. The p7, a hydrophobic integral membrane [134] viroprotein [135] of HCV, localizes to mitochondria [66] and controls membrane permeability to cations [66, 136] promoting cell survival for virus replication [135].

The R (Vpr) protein of HIV, a small accessory protein, localizes to the mitochondria, interacts with ANT, modulates MPTP, and induces loss of MMP promoting release of Cyto C [137] leading to cell death [138, 139]. The Tat protein of HIV also modulates MPTP leading to the accumulation of Tat in mitochondria and induction of loss of MMP resulting in caspase dependent apoptosis [140].

The M11L protein of myxoma poxvirus localizes to the mitochondria, interacts with the mitochondrial peripheral benzodiazepine receptor (PBR), and regulates MPTP [141] inhibiting MMP loss [142] and thus inhibiting induction of apoptosis during viral infection [143]. The FIL protein of vaccinia virus downregulates proapoptotic Bcl-2 family protein Bak and, inhibits the loss of the MMP and the release of Cyt-C [144, 145]. The crmA/Spi-2 protein of vaccinia virus, a caspase 8 inhibitor, modulates MPTP thus preventing apoptosis [146].

The PB1-F2 protein of influenza A viruses localizes to the mitochondria [147–150] and interacts with VDAC1 and ANT3 [151] resulting in decreased MMP, which induces the release of proapoptotic proteins causing cell death. Recent evidence shows that PB1-F2 is also able to form nonselective protein channel pores resulting in the alteration of mitochondrial morphology, dissipation of MMP, and cell death [150]. The M2 protein of influenza virus, a viroprotein, causes the alteration of mitochondrial morphology, dissipation of MMP, and cell death (reviewed by [135]).

The p13II, an accessory protein encoded by x-II ORF of human T-lymphotropic virus (HTLV), a new member of the viroprotein family [152], localizes to the mitochondria of infected cells and increases the MMP leading to apoptosis [153] and mitochondrial swelling [153–155].

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

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

5. Viruses Regulate Apoptosis

5.1. Apoptosis

During the coevolution of viruses with their hosts, viruses have developed several strategies to manipulate the host cell machinery for their survival, replication, and release from the cell. Viruses target the cellular apoptotic machinery at critical stages of viral replication to meet their ends [157, 158]. Depending upon the need, a virus may inhibit [159] or induce [160] apoptosis for the obvious purpose of replication and spread, respectively [158, 159]. Interference in mitochondrial function can cause either cell death due to deregulation of the Ca²⁺ signaling pathways and ATP depletion or apoptosis due to regulation of Bcl-2 family proteins. Apoptosis is a programmed cell death [161] characterized by membrane blebbing, condensation of the nucleus and cytoplasm, and endonucleosomal DNA cleavage. The process starts as soon as the cell senses physiological or stress stimuli, which disturbs the homeostasis of the cell [162, 163]. Apoptotic cell death can be considered as an innate response to limit the growth of microorganisms including viruses attacking the cell.

Two major pathways, namely, the extrinsic and the intrinsic are involved in triggering apoptosis [163, 164]. The extrinsic pathway is mediated by signaling through death receptors like tumor necrosis factor or Fas ligand receptor causing the assembly of death inducing signaling complex (DISC) with the recruitment of proteins like caspases leading to the mitochondrial membrane permeabilization. In 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 [165, 166], which recruits APAF1 [167, 168] resulting in direct activation of caspase 9 [35, 169]. Both the extrinsic and the intrinsic processes congregate at the activation of downstream effector caspases, (i.e., caspase-3) [170] which is responsible for inducing the morphological changes observed in an apoptotic cell. In addition to Cyt-C, Smac/DIABLO as well as caspase independent death effectors inducing factor (AIF) and endonuclease G [171–173] acts as an activator of the caspase.

The B cell lymphoma- (Bcl-) 2 family of proteins tightly regulate the apoptotic events involving the mitochondria [174, 175]. More than 20 mammalian Bcl-2 family proteins have been described to date [176, 177]. They have been classified by the presence of Bcl-2 homology (BH) domains arranged in the order BH4-BH3-BH2-BH1 and the C-terminal hydrophobic transmembrane (TM) domain, which anchors them to the outer mitochondrial membrane [178]. The highly conserved BH1 and BH2 domains are responsible for antiapoptotic activity and multimerization of Bcl-2 family proteins. The BH3 domain is mainly responsible for proapoptotic activity and the less conserved BH4 domain is required for the antiapoptotic activities of Bcl-2 and proteins [174, 178]. Most of the antiapoptotic proteins are multidomain proteins, which contain all four BH domains (BH1 to BH4) and a TM domain. In contrast, proapoptotic proteins are either multidomain proteins, which contain three BH domains (BH1 to BH3) or single domain proteins, which contain one domain (BH3) [158]. The Bcl-2 proteins regulate the MMP depending upon whether they belong to the pro- or antiapoptotic branch of the family, respectively. The MMP marks the dead end of apoptosis beyond which cells are destined to die [125, 166, 179–183].

5.2. Regulation by Viruses

Viruses encode homologs of Bcl-2 (vBcl-2) proteins, which can induce (pro-apototic) or prevent (antiapoptotic) apoptosis thus helping viruses to complete their life cycle in the host cells [117, 163, 175]. While the vBcl-2s and the cellular Bcl-2s share limited sequence homology, their secondary structures are predicted to be quite similar [158, 174, 184]. During primary infection, interplay between vBcl-2 and other proteins enhances the lifespan of the host cells resulting in efficient production of viral progeny and ultimately spread of infection to the new cells. It also favors viral persistence in the cells by enabling the latently infecting viruses to make the transition to productive infection. The pathways and strategies used by viruses to induce/inhibit apoptosis have been reviewed earlier [185].

Many viruses encode for the homologs of antiapoptotic Bcl-2 proteins, which preferentially localize to the mitochondria and may interact with the other proapoptotic Bax homologues. The E1B19K encoded by human-adenovirus- (HAdV-) 5 contains BH1 and BH3-like domains and blocks TNF-alpha-mediated death signaling by inhibiting a form of Bax that interrupts the caspase activation downstream of caspase-8 and upstream of caspase-9 [186, 187]. Like HAdV-5 E1B19K [186], some viruses encode Bcl-2 homologues lacking BH4 domain, which are thought to act by inhibiting proapoptotic members of Bcl-2 family proteins. The FPV309 protein encoded by fowl pox virus contains highly conserved BH1 and BH2-like domains, and a cryptic BH3 domain, interacts with Bax protein and inhibits apoptosis [188]. The A179L protein encoded by African swine fever virus (ASFV) contains BH1 and BH2 domains and, interacts with Bax-Bak proteins and inhibits apoptosis [189, 190]. The Bcl-2 homolog (vBcl-2) encoded by Herpesvirus saimiri (HVS) contains BH3 and BH4-like domains and interacts with Bax, thus stabilizing mitochondria against a variety of apoptotic stimuli preventing the cell death [191]. The E4 ORF encoded by equine Herpesvirus-3 contains BH1 and BH2 domains [192], which may interact with Bax and be essential for antiapoptotic activity [193].

Viruses also encode homologs of proapoptotic Bcl-2 proteins. The HBV encodes protein X, a vBcl-2 protein containing BH3, which localizes to the mitochondria and interacts with VDACs inducing the loss of the MMP leading to apoptosis [117, 121, 194, 195] or interacts with Hsp60 and induces apoptosis [196]. In contrast, another study revealed the protective effects of HB-X in response to proapoptotic stimuli (Fas, TNF, and serum withdrawal) but not from chemical apoptotic stimuli [197]. The protein X of HBV is known to stimulate NFκB [198, 199], SAPK [200, 201], and PI3K/PKB [202] to prevent apoptosis. It is possible that the diverse functions of HBV protein X occur at different times of virus replication cycle in the infected cells. The BALF1 protein encoded by EBV contains BH1 and BH4 domains [203], which interacts with the Bax-Bak proteins [192] and inhibits the antiapoptotic activity of the EBV BHRF1 and the Kaposi Sarcoma virus (KSV) Bcl-2 protein, both of which contain BH1 and BH2 domains [204] and interact with BH3 only proteins [205].

The effects of viral Bcl-2 homologues are thus apparently centered around mitochondria and include prevention or induction of MMP loss. The induction of MMP loss leads to the release of Cyto C and other proapoptotic signals into the cytosol and activation of downstream caspases leading to the cell death and dissemination of viruses to neighbouring cells for further infection.

Viruses encode pro/anti apoptotic proteins, which show no homology to Bcl-2 proteins [158]. The E6 protein of human papilloma virus (HPV) downregulates Bax signal upstream of mitochondria [206, 207] and prevents the release of Cyto C, AIF, and Omi, thus preventing apoptosis [208]. This E6 activity towards another Bcl2 family proapoptotic protein Bak is a key factor promoting the survival of HPV-infected cells, which in turn facilitates the completion of viral life cycle [207]. Enterovirus (EV) 71 induces conformational changes in Bax and increases its expression in cells following infection and induces the activation of caspases 3, 8, and PARP causing caspase dependent apoptosis [209]. On the contrary, Rubella viral capsid binds to Bax, forms oligoheteromers, and prevents the formation of pores on mitochondrial membrane thus preventing Bax induced apoptosis [210].

Viruses also encode proteins, which act as viral mitochondrial inhibitors of apoptosis (vMIA) thus protecting the cells. A splice variant of UL37 of HCMV acts as vMIA and protects the cells from apoptosis [211] thereby helping viruses to complete their replication cycle. It localizes to mitochondria and interacts with ANT [211] and Bax [212, 213]. HCMV vMIA has an N-terminal mitochondrial localization domain and a C-terminal antiapoptotic domain [211], which recruits Bax to mitochondria and prevents loss of MMP. It protects the cells against CD95 ligation [211] and oxidative stress-induced cell death [214, 215] and prevents mitochondrial fusion [216] thus promoting cell survival.

vMIA does not inhibit the apoptotic events upstream of mitochondria but can influence events like preservation of ATP generation, inhibition of Cyto C release, and caspase 9 activation, following induction of apoptosis. However, the exact mechanisms of the events around vMIA still remain a question.

6. Viruses Modulate Mitochondrial Antiviral Immunity

6.1. Mitochondrial Antiviral Immunity

Cells respond to virus attack by activating a variety of signal transduction pathways leading to the production of interferons [217], which limit or eliminate the invading virus. The presence of viruses inside the cell is first sensed by pattern recognition receptors (PRRs) that recognize the pathogen associated molecular patterns (PAMPs). PRRs include toll-like receptors (TLRs), nucleotide oligomerization domain (NOD) like receptors (NLRs), and retinoic acid-inducible gene I (RIG-I) like receptors (RLRs). Mitochondria have been associated with RLRs, which include retinoic acid-inducible gene I (RIG-I) [218] and melanoma differentiation-associated gene 5 (Mda-5) [219]. Both are cytoplasm-located RNA helicases that recognize dsRNA. The N-terminus of RIG-1 has caspase activation and recruitment domains (CARDs) whereas C-terminus has RNA helicase activity [218], which recognizes and binds to uncapped and unmodified RNA generated by viral polymerases 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 [220] triggering NFκB production. RLRs have recently been reviewed in detail [221–223].

A CARD domain containing protein named mitochondrial antiviral signaling (MAVS) [15, 224], virus-induced signaling adaptor (VISA) [225], IFN-β promoter stimulator 1 (IPS-1) [226], or CARD adaptor inducing IFN-β (CARDIF) protein [227] acts downstream of the RIG-I. Besides the presence of N-terminal CARD domain, MAVS contains a proline-rich region and a C-terminal hydrophobic transmembrane (TM) region, which targets the protein to the mitochondrial outer membrane and is critical for its activity [15]. The TM region of the MAVS resembles the TM domains of many C-terminal tail-anchored proteins on the outer membrane of the mitochondria including Bcl-2 and Bcl-xL [15]. Recent reports indicate that MAVS has an important role in inducing the antiviral defenses in the cell. Overexpression of MAVS leads to the activation of NFκB and IRF-3, leading to the induction of type I interferon response, which is abrogated in the absence of MAVS [15] thus indicating the specific role of MAVS in inducing antiviral response. MAVS has also been shown to prevent apoptosis by its interaction with VDAC [228] and preventing the opening of MPTP.

6.2. Regulation by Viruses

Some viruses induce cleavage of MAVs from outer membranes of mitochondria [227, 229] thus greatly reducing their ability to induce interferon response. HCV persists in the host by lowering the host cell immune response including inhibiting the production of IFN-β by RIG-I pathway [230–232]. The NS3/4A protein of HCV colocalizes with mitochondrial MAVS [227, 229] leading to the cleavage of MAVS at amino acid 508. Since free form of the MAVS is not functional, the dislodging of MAV from the mitochondria inactivates MAVS [227] thus helping in paralyzing the host defense against HCV. Interestingly, another member of family Flaviviridae GB virus B shares 28% amino acid homology with HCV over the lengths of their open-reading frames [233]. The NS3/4A protein of GB virus also cleaves MAVS in a manner similar to HCV, thus effectively compromising the host immune response by preventing the production of interferons [234]. Other viruses like influenza A translocate RIG-I/MAVS components to the mitochondria of infected human primary macrophages and regulate the antiviral/apoptotic signals increasing the viral survivability [235].

7. Viruses Hijack Host Mitochondrial Proteins

Over the years, viruses have perfected different strategies to establish complex relationships with their host with the sole purpose of preserving their existence. One such strategy involves the hijacking of the host cell mitochondrial proteins. The p32, a mitochondria-associated cellular protein, is a member of a complex involved in the import of cytosolic proteins to the nucleus. Upon entry into the cell, adenovirus hijacks this protein and piggybacks it to transport its genome to the nucleus [236], thereby increasing its chances of survival and establishment in the host cell. During HIV-1 assembly, iso-acceptors are selectively incorporated into virions, and binds to HIV genome and is used as the primer for reverse transcription [237]. In humans, a single gene produces both cytoplasmic and mitochondrial Lys tRNA synthetases (LysRSs) by alternative splicing [238]. The mitochondrial LysRS is produced as a preprotein, which is transported into the mitochondria. The premitochondrial or mitochondrial LysRS is specifically packaged into HIV [239] and acts as a primer to initiate the replication of HIV-I RNA genome, which then binds to a site complementary to the 3′-end 18 nucleotides of . It is proposed that HIV viral protein R (Vpr) alters the permeability of the mitochondria [138] leading to the release of premito- or mito-LysRS, which then interacts with Vpr [240] and gets packed into the progeny virions.

Viperin, an interferon inducible protein, is induced in the cells in response to viral infection [241]. This protein has been shown to prevent the release of influenza virus particles from the cells by trapping them in lipid rafts inside the cells thereby preventing its dissemination [242]. During infection, HCMV induces IFN independent expression of viperin, which interacts with HCMV encoded vMIA protein resulting in relocation of viperin from ER to mitochondria. In mitochondria, viperin interacts with mitochondrial tri-functional protein and decreases ATP generation by disrupting oxidation of fatty acids, which results in disrupting actin cytoskeleton of the cells and enhancing the viral infectivity [243].

8. Viruses Alter Intracellular Distribution of Mitochondria

Viruses alter the intracellular distribution of mitochondria either by concentrating the mitochondria near the viral factories to meet energy requirements during viral replication or by cordoning off the mitochondria within cytoplasm to prevent the release of mediators of apoptosis. The protein X of HBV causes microtubule mediated perinuclear clustering of the mitochondria by p38 mitogen-activated protein kinase (MAPK) mediated dynein activity [244]. HCV nonstructural protein 4A (NS4A) either alone or together with NS3, (in the form of the NS3/4A polyprotein) accumulates on mitochondria and changes their intracellular distribution [245]. HIV-1 infection causes clustering of the mitochondria in the infected cells [246]. Interestingly, ASFV causes the microtubule-mediated clustering of the mitochondria around virus factories in the cell providing energy for virus release [247]. Similar changes were observed in the chick embryo fibroblasts infected with frog virus 3, where degenerate mitochondria surrounding virus factories were found [248].

9. Viruses Mimic the Host Mitochondrial Proteins

Molecular mimicry is “the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides” [249, 250]. Since structure follows the function, viruses, during their coevolution with hosts have evolved to mimic the host proteins to meet their ends during progression of their life cycle inside the cell. Mimicking aids the viruses to gain access to host cellular machinery and greatly helps in their survival in the hostile host environment.

Mimivirus, a member of the newly created virus family Mimiviridae, encodes a eukaryotic mitochondria carrier protein (VMC-I) [251], which mimics the host cell’s mitochondrial carrier protein and thus controls the mitochondrial transport machinery in infected cells. It helps to transport ADP, dADP, TTP, dTTP, and UTP in exchange for dATP, thus exploiting the host for energy requirements during replication of its A+T rich genome [251]. Besides VMC-I, mimivirus encodes several other proteins (L359, L572, R776, R596, R740, R824 L81, R151, R900, and L908) with putative mitochondria localization signals, which suggest that mimivirus has evolved a strategy to take over the host mitochondria and exploited its physiology to compensate for its energy requirements and biogenesis [251]. Viral Bcl-2 homologues (vBcl-2) are other groups of viral proteins that mimic the host cell Bcl-2s and have been described elsewhere in this review.

10. Viruses Cause Host Mitochondrial DNA Depletion

Mammalian mitochondria contain a small circular genome, which synthesizes enzymes for oxidative phosphorylation and mitochondrial RNAs (mtRNAs) [27]. To increase the chance of survival, some viruses appear to have adopted the strategy of damaging the host cell mitochondrial DNA. Since mitochondria act as a source of energy and play an important role in antiviral immunity as well, it is possible that damage to mitochondrial DNA may help in evading mitochondrial antiviral immune responses [252].

During productive infection of mammalian cells in vitro, HSV-1 induces the rapid and complete degradation of host mitochondrial DNA [252]. The UL12.5 protein of HSV-1 localizes to the mitochondria and induces DNA depletion in the absence of other viral gene products [252, 253]. The immediate early Zta protein of EBV interacts with mitochondrial single stranded DNA binding protein resulting in reduced mitochondrial DNA (mtDNA) replication and enhanced viral DNA replication [254]. HCV causes the reactive oxygen species and nitrous oxide mediated DNA damage in host mtDNA [107, 255]. Interestingly, depletion of mtDNA has also been observed in HIV/HCV coinfected humans [256].

11. Conclusions

Though progress has been made in understanding the interaction of viruses with mitochondria-mediated pathways, the pathways linking the detection of viral infection by PRRs (or exact mechanism by which PRRs recognize the PAMPs) and their link to mitochondria-mediated cell death remain poorly understood. Role of the mitochondria in immunity and viral mechanisms to evade them highlights the fact that even after billions of years of coevolution, the fight for the survival is still going on. Both the host and the viruses are evolving, finding new ways to survive. It may be interesting to note that mitochondria mediated apoptosis might be an evolutionary adaptation by which they might have effectively prevented the entry of other microorganisms trying to gain entry into the host cell and thus effectively establishing themselves as an integral part of the cell.

Acknowledgments

The authors thank Dr. Vikram Misra, Veterinary Microbiology, University of Saskatchewan, for his vision and advice. They thank Sherry Hueser for carefully proofreading the paper. The paper is published with the permission of Director VIDO as VIDO article no. 617. Suresh K. Tikoo is funded by grants from Natural Sciences and Engineering Research Council of Canada.

References

D. C. Wallace, “A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine,” Annual Review of Genetics, vol. 39, pp. 359–407, 2005.
View at: Publisher Site | Google Scholar
D. C. Chan, “Mitochondria: dynamic organelles in disease, aging, and development,” Cell, vol. 125, no. 7, pp. 1241–1252, 2006.
View at: Publisher Site | Google Scholar
A. Antignani and R. J. Youle, “How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane?” Current Opinion in Cell Biology, vol. 18, no. 6, pp. 685–689, 2006.
View at: Publisher Site | Google Scholar
H. Chen and D. C. Chan, “Emerging functions of mammalian mitochondrial fusion and fission,” Human Molecular Genetics, vol. 14, no. 2, pp. R283–R289, 2005.
View at: Publisher Site | Google Scholar
I. Gradzka, “Mechanisms and regulation of the programmed cell death,” Postepy Biochemii, vol. 52, no. 2, pp. 157–165, 2006.
View at: Google Scholar
H. M. McBride, M. Neuspiel, and S. Wasiak, “Mitochondria: more than just a powerhouse,” Current Biology, vol. 16, no. 14, pp. R551–R560, 2006.
View at: Publisher Site | Google Scholar
G. Kroemer, L. Galluzzi, and C. Brenner, “Mitochondrial membrane permeabilization in cell death,” Physiological Reviews, vol. 87, no. 1, pp. 99–163, 2007.
View at: Publisher Site | Google Scholar
C. A. Mannella, “Structure and dynamics of the mitochondrial inner membrane cristae,” Biochimica et Biophysica Acta, vol. 1763, no. 5-6, pp. 542–548, 2006.
View at: Publisher Site | Google Scholar
D. G. Hardie, J. W. Scott, D. A. Pan, and E. R. Hudson, “Management of cellular energy by the AMP-activated protein kinase system,” The FEBS Letters, vol. 546, no. 1, pp. 113–120, 2003.
View at: Publisher Site | Google Scholar
R. G. Jones, D. R. Plas, S. Kubek et al., “AMP-activated protein kinase induces a p53-dependent metabolic checkpoint,” Molecular Cell, vol. 18, no. 3, pp. 283–293, 2005.
View at: Publisher Site | Google Scholar
S. Mandal, P. Guptan, E. Owusu-Ansah, and U. Banerjee, “Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in Drosophila,” Developmental Cell, vol. 9, no. 6, pp. 843–854, 2005.
View at: Publisher Site | Google Scholar
L. E. Bakeeva, Y. S. Chentsov, and V. P. Skulachev, “Mitochondrial framework (reticulum mitochondriale) in rat diaphragm muscle,” Biochimica et Biophysica Acta, vol. 501, no. 3, pp. 349–369, 1978.
View at: Google Scholar
L. E. Bakeeva, Y. S. Chentsov, and V. P. Shulachev, “Intermitochondrial contacts in myocardiocytes,” Journal of Molecular and Cellular Cardiology, vol. 15, no. 7, pp. 413–420, 1983.
View at: Google Scholar
S. Honda and S. Hirose, “Stage-specific enhanced expression of mitochondrial fusion and fission factors during spermatogenesis in rat testis,” Biochemical and Biophysical Research Communications, vol. 311, no. 2, pp. 424–432, 2003.
View at: Publisher Site | Google Scholar
R. B. Seth, L. Sun, C. K. Ea, and Z. J. Chen, “Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF3,” Cell, vol. 122, no. 5, pp. 669–682, 2005.
View at: Publisher Site | Google Scholar
E. Bossy-Wetzel, M. J. Barsoum, A. Godzik, R. Schwarzenbacher, and S. A. Lipton, “Mitochondrial fission in apoptosis, neurodegeneration and aging,” Current Opinion in Cell Biology, vol. 15, no. 6, pp. 706–716, 2003.
View at: Publisher Site | Google Scholar
C. W. Olanow and W. G. Tatton, “Etiology and pathogenesis of Parkinson's disease,” Annual Review of Neuroscience, vol. 22, pp. 123–144, 1999.
View at: Publisher Site | Google Scholar
S. K. van den Eeden, C. M. Tanner, A. L. Bernstein et al., “Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity,” The American Journal of Epidemiology, vol. 157, no. 11, pp. 1015–1022, 2003.
View at: Google Scholar
L. J. Martin, “Mitochondriopathy in Parkinson disease and amyotrophic lateral sclerosis,” Journal of Neuropathology and Experimental Neurology, vol. 65, no. 12, pp. 1103–1110, 2006.
View at: Publisher Site | Google Scholar
R. McFarland, R. W. Taylor, and D. M. Turnbull, “Mitochondrial disease—its impact, etiology, and pathology,” in Current Topics in Developmental Biology, J. C. St John, Ed., pp. 113–155, Academic Press, New York, NY, USA, 2007.
View at: Google Scholar
D. Rapaport, “Finding the right organelle. Targeting signals in mitochondrial outer-membrane proteins,” EMBO Reports, vol. 4, no. 10, pp. 948–952, 2003.
View at: Publisher Site | Google Scholar
M. Amiry-Moghaddam, H. Lindland, S. Zelenin et al., “Brain mitochondria contain aquaporin water channels: evidence for the expression of a short AQP9 isoform in the inner mitochondrial membrane,” FASEB Journal, vol. 19, no. 11, pp. 1459–1467, 2005.
View at: Publisher Site | Google Scholar
G. Calamita, D. Ferri, P. Gena et al., “The inner mitochondrial membrane has aquaporin-8 water channels and is highly permeable to water,” The Journal of Biological Chemistry, vol. 280, no. 17, pp. 17149–17153, 2005.
View at: Publisher Site | Google Scholar
B. Yang, D. Zhao, and A. S. Verkman, “Evidence against functionally significant aquaporin expression in mitochondria,” The Journal of Biological Chemistry, vol. 281, no. 24, pp. 16202–16206, 2006.
View at: Publisher Site | Google Scholar
G. S. Shadel and D. A. Clayton, “Mitochondrial DNA maintenance in vertebrates,” Annual Review of Biochemistry, vol. 66, pp. 409–435, 1997.
View at: Publisher Site | Google Scholar
E. A. Shoubridge, “The ABcs of mitochondrial transcription,” Nature Genetics, vol. 31, no. 3, pp. 227–228, 2002.
View at: Publisher Site | Google Scholar
G. Burger, M. W. Gray, and B. F. Lang, “Mitochondrial genomes: anything goes,” Trends in Genetics, vol. 19, no. 12, pp. 709–716, 2003.
View at: Publisher Site | Google Scholar
W. Neupert and J. M. Herrmann, “Translocation of proteins into mitochondria,” Annual Review of Biochemistry, vol. 76, pp. 723–749, 2007.
View at: Publisher Site | Google Scholar
A. Chacinska, C. M. Koehler, D. Milenkovic, T. Lithgow, and N. Pfanner, “Importing mitochondrial proteins: machineries and mechanisms,” Cell, vol. 138, no. 4, pp. 628–644, 2009.
View at: Publisher Site | Google Scholar
O. Schmidt, N. Pfanner, and C. Meisinger, “Mitochondrial protein import: from proteomics to functional mechanisms,” Nature Reviews Molecular Cell Biology, vol. 11, no. 9, pp. 655–667, 2010.
View at: Publisher Site | Google Scholar
M. van der Laan, D. P. Hutu, and P. Rehling, “On the mechanism of preprotein import by the mitochondrial presequence translocase,” Biochimica et Biophysica Acta, vol. 1803, no. 6, pp. 732–739, 2010.
View at: Publisher Site | Google Scholar
S. J. Habib, T. Waizenegger, M. Lech, W. Neupert, and D. Rapaport, “Assembly of the TOB complex of mitochondria,” The Journal of Biological Chemistry, vol. 280, no. 8, pp. 6434–6440, 2005.
View at: Publisher Site | Google Scholar
T. Schwann, “Microscopical researches into the accordance in the structure and growth of animals and plants,” in Contributions to Phytogenesis, M. J. Schleiden, Ed., Sydenham Society, London, UK, 1847.
View at: Google Scholar
M. J. Berridge, M. D. Bootman, and P. Lipp, “Calcium—a life and death signal,” Nature, vol. 395, no. 6703, pp. 645–648, 1998.
View at: Publisher Site | Google Scholar
D. R. Green and J. C. Reed, “Mitochondria and apoptosis,” Science, vol. 281, no. 5381, pp. 1309–1312, 1998.
View at: Google Scholar
S. V. Chorna, V. I. Dosenko, N. A. Strutyns'ka, H. L. Vavilova, and V. F. Sahach, “Increased expression of voltage-dependent anion channel and adenine nucleotide translocase and the sensitivity of calcium-induced mitochondrial permeability transition opening pore in the old rat heart,” Fiziolohichnyǐ Zhurnal, vol. 56, no. 4, pp. 19–25, 2010.
View at: Google Scholar
Y. Liu, L. Gao, Q. Xue et al., “Voltage-dependent anion channel involved in the mitochondrial calcium cycle of cell lines carrying the mitochondrial DNA A4263G mutation,” Biochemical and Biophysical Research Communications, vol. 404, no. 1, pp. 364–369, 2011.
View at: Publisher Site | Google Scholar
Y. Kirichok, G. Krapivinsky, and D. E. Clapham, “The mitochondrial calcium uniporter is a highly selective ion channel,” Nature, vol. 427, no. 6972, pp. 360–364, 2004.
View at: Publisher Site | Google Scholar
T. E. Gunter and K. K. Gunter, “Uptake of calcium by mitochondria: transport and possible function,” IUBMB Life, vol. 52, no. 3–5, pp. 197–204, 2002.
View at: Publisher Site | Google Scholar
G. Szabadkai, K. Bianchi, P. Várnai et al., “Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca²⁺ channels,” Journal of Cell Biology, vol. 175, no. 6, pp. 901–911, 2006.
View at: Publisher Site | Google Scholar
A. P. Halestrap, “What is the mitochondrial permeability transition pore?” Journal of Molecular and Cellular Cardiology, vol. 46, no. 6, pp. 821–831, 2009.
View at: Publisher Site | Google Scholar
A. P. Halestrap, “A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection,” Biochemical Society Transactions, vol. 38, no. 4, pp. 841–860, 2010.
View at: Publisher Site | Google Scholar
M. Hüttemann, I. Lee, A. Pecinova, P. Pecina, K. Przyklenk, and J. W. Doan, “Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease,” Journal of Bioenergetics and Biomembranes, vol. 40, no. 5, pp. 445–456, 2008.
View at: Publisher Site | Google Scholar
V. Petronilli, B. Persson, M. Zoratti, J. Rydstrom, and G. F. Azzone, “Flow-force relationships during energy transfer between mitochondrial proton pumps,” Biochimica et Biophysica Acta, vol. 1058, no. 2, pp. 297–303, 1991.
View at: Google Scholar
W. Xia, Y. Shen, H. Xie, and S. Zheng, “Involvement of endoplasmic reticulum in hepatitis B virus replication,” Virus Research, vol. 121, no. 2, pp. 116–121, 2006.
View at: Publisher Site | Google Scholar
W. J. H. Koopman, L. G. J. Nijtmans, C. E. J. Dieteren et al., “Mammalian mitochondrial complex I: biogenesis, regulation, and reactive oxygen species generation,” Antioxidants and Redox Signaling, vol. 12, no. 12, pp. 1431–1470, 2010.
View at: Publisher Site | Google Scholar
S. A. Susin, H. K. Lorenzo, N. Zamzami et al., “Molecular characterization of mitochodrial apoptosis-inducing factor,” Nature, vol. 397, no. 6718, pp. 441–446, 1999.
View at: Publisher Site | Google Scholar
R. S. Balaban, “The role of Ca²⁺ signaling in the coordination of mitochondrial ATP production with cardiac work,” Biochimica et Biophysica Acta, vol. 1787, no. 11, pp. 1334–1341, 2009.
View at: Publisher Site | Google Scholar
M. E. Wernette, R. S. Ochs, and H. A. Lardy, “Ca²⁺ stimulation of rat liver mitochondrial glycerophosphate dehydrogenase,” The Journal of Biological Chemistry, vol. 256, no. 24, pp. 12767–12771, 1981.
View at: Google Scholar
J. G. McCormack and R. M. Denton, “Mitochondrial Ca²⁺ transport and the role of intramitochondrial Ca²⁺ in the regulation of energy metabolism,” Developmental Neuroscience, vol. 15, no. 3–5, pp. 165–173, 1993.
View at: Google Scholar
V. Mildaziene, R. Baniene, Z. Nauciene et al., “Calcium indirectly increases the control exerted by the adenine nucleotide translocator over 2-oxoglutarate oxidation in rat heart mitochondria,” Archives of Biochemistry and Biophysics, vol. 324, no. 1, pp. 130–134, 1995.
View at: Publisher Site | Google Scholar
R. A. Haworth, D. R. Hunter, and H. A. Berkoff, “Contracture in isolated adult rat heart cells. Role of Ca²⁺, ATP, and compartmentation,” Circulation Research, vol. 49, no. 5, pp. 1119–1128, 1981.
View at: Google Scholar
J. A. Copello, S. Barg, A. Sonnleitner et al., “Differential activation by Ca²⁺, ATP and caffeine of cardiac and skeletal muscle ryanodine receptors after block by Mg²⁺,” Journal of Membrane Biology, vol. 187, no. 1, pp. 51–64, 2002.
View at: Publisher Site | Google Scholar
P. Nasr, H. I. Gursahani, Z. Pang et al., “Influence of cytosolic and mitochondrial Ca²⁺, ATP, mitochondrial membrane potential, and calpain activity on the mechanism of neuron death induced by 3-nitropropionic acid,” Neurochemistry International, vol. 43, no. 2, pp. 89–99, 2003.
View at: Publisher Site | Google Scholar
J. D. Johnston and M. D. Brand, “The mechanism of Ca²⁺ stimulation of citrulline and N-acetylglutamate synthesis by mitochondria,” Biochimica et Biophysica Acta, vol. 1033, no. 1, pp. 85–90, 1990.
View at: Publisher Site | Google Scholar
J. D. McGivan, N. M. Bradford, and J. Mendes-Mourão, “The regulation of carbamoyl phosphate synthase activity in rat liver mitochondria,” Biochemical Journal, vol. 154, no. 2, pp. 415–421, 1976.
View at: Google Scholar
T. I. Peng and M. J. Jou, “Oxidative stress caused by mitochondrial calcium overload,” Annals of the New York Academy of Sciences, vol. 1201, pp. 183–188, 2010.
View at: Publisher Site | Google Scholar
K. Lund and B. Ziola, “Cell sonicates used in the analysis of how measles and herpes simplex type 1 virus infections influence Vero cell mitochondrial calcium uptake,” Canadian Journal of Biochemistry and Cell Biology, vol. 63, no. 11, pp. 1194–1197, 1985.
View at: Google Scholar
Y. Li, D. F. Boehning, T. Qian, V. L. Popov, and S. A. Weinman, “Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca²⁺ uniporter activity,” FASEB Journal, vol. 21, no. 10, pp. 2474–2485, 2007.
View at: Publisher Site | Google Scholar
R. V. Campbell, Y. Yang, T. Wang et al., “Effects of hepatitis C core protein on mitochondrial electron transport and production of reactive oxygen species,” Methods in Enzymology, vol. 456, pp. 363–380, 2009.
View at: Publisher Site | Google Scholar
G. Gong, G. Waris, R. Tanveer, and A. Siddiqui, “Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-κB,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 17, pp. 9599–9604, 2001.
View at: Publisher Site | Google Scholar
M. Kalamvoki and P. Mavromara, “Calcium-dependent calpain proteases are implicated in processing of the hepatitis C virus NS5A protein,” Journal of Virology, vol. 78, no. 21, pp. 11865–11878, 2004.
View at: Publisher Site | Google Scholar
N. Dionisio, M. V. Garcia-Mediavilla, S. Sanchez-Campos et al., “Hepatitis C virus NS5A and core proteins induce oxidative stress-mediated calcium signalling alterations in hepatocytes,” Journal of Hepatology, vol. 50, no. 5, pp. 872–882, 2009.
View at: Publisher Site | Google Scholar
M. K. Baum, S. Sales, D. T. Jayaweera et al., “Coinfection with hepatitis C virus, oxidative stress and antioxidant status in HIV-positive drug users in Miami,” HIV Medicine, vol. 12, no. 2, pp. 78–86, 2011.
View at: Publisher Site | Google Scholar
G. A. Cook and S. J. Opella, “NMR studies of p7 protein from hepatitis C virus,” European Biophysics Journal, vol. 39, no. 7, pp. 1097–1104, 2010.
View at: Publisher Site | Google Scholar
S. D. C. Griffin, R. Harvey, D. S. Clarke, W. S. Barclay, M. Harris, and D. J. Rowlands, “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,” Journal of General Virology, vol. 85, no. 2, pp. 451–461, 2004.
View at: Publisher Site | Google Scholar
M. J. Bouchard, L. H. Wang, and R. J. Schneider, “Calcium signaling by HBx protein in hepatitis B virus DNA replication,” Science, vol. 294, no. 5550, pp. 2376–2378, 2001.
View at: Publisher Site | Google Scholar
Y. Choi, S. G. Park, J. H. Yoo, and G. Jung, “Calcium ions affect the hepatitis B virus core assembly,” Virology, vol. 332, no. 1, pp. 454–463, 2005.
View at: Publisher Site | Google Scholar
M. Foti, L. Cartier, V. Piguet et al., “The HIV Nef protein alters Ca²⁺ signaling in myelomonocytic cells through SH3-mediated protein-protein interactions,” The Journal of Biological Chemistry, vol. 274, no. 49, pp. 34765–34772, 1999.
View at: Publisher Site | Google Scholar
A. Manninen and K. Saksela, “HIV-1 Nef interacts with inositol trisphosphate receptor to activate calcium signaling in T cells,” Journal of Experimental Medicine, vol. 195, no. 8, pp. 1023–1032, 2002.
View at: Publisher Site | Google Scholar
S. Kinoshita, L. Su, M. Amano, L. A. Timmerman, H. Kaneshima, and G. P. Nolan, “The T cell activation factor NF-ATc positively regulates HIV-1 replication and gene expression in T cells,” Immunity, vol. 6, no. 3, pp. 235–244, 1997.
View at: Publisher Site | Google Scholar
M. C. Ruiz, J. Cohen, and F. Michelangeli, “Role of Ca²⁺ in the replication and pathogenesis of rotavirus and other viral infections,” Cell Calcium, vol. 28, no. 3, pp. 137–149, 2000.
View at: Publisher Site | Google Scholar
P. Tian, M. K. Estes, Y. Hu, J. M. Ball, C. Q. Zeng, and W. P. Schilling, “The rotavirus nonstructural glycoprotein NSP4 mobilizes Ca²⁺ from the endoplasmic reticulum,” Journal of Virology, vol. 69, no. 9, pp. 5763–5772, 1995.
View at: Google Scholar
Y. Díaz, M. E. Chemello, F. Peña et al., “Expression of nonstructural rotavirus protein NSP4 mimics Ca²⁺ homeostasis changes induced by rotavirus infection in cultured cells,” Journal of Virology, vol. 82, no. 22, pp. 11331–11343, 2008.
View at: Publisher Site | Google Scholar
J. L. Zambrano, Y. Díaz, F. Peña et al., “Silencing of rotavirus NSP4 or VP7 expression reduces alterations in Ca²⁺ homeostasis induced by infection of cultured cells,” Journal of Virology, vol. 82, no. 12, pp. 5815–5824, 2008.
View at: Publisher Site | Google Scholar
M. C. Ruiz, O. C. Aristimuño, Y. Díaz et al., “Intracellular disassembly of infectious rotavirus particles by depletion of Ca²⁺ sequestered in the endoplasmic reticulum at the end of virus cycle,” Virus Research, vol. 130, no. 1-2, pp. 140–150, 2007.
View at: Publisher Site | Google Scholar
A. Irurzun, J. Arroyo, A. Alvarez, and L. Carrasco, “Enhanced intracellular calcium concentration during poliovirus infection,” Journal of Virology, vol. 69, no. 8, pp. 5142–5146, 1995.
View at: Google Scholar
R. Aldabe, A. Irurzun, and L. Carrasco, “Poliovirus protein 2BC increases cytosolic free calcium concentrations,” Journal of Virology, vol. 71, no. 8, pp. 6214–6217, 1997.
View at: Google Scholar
C. Brisac, F. Téoulé, A. Autret et al., “Calcium flux between the endoplasmic reticulum and mitochondrion contributes to poliovirus-induced apoptosis,” Journal of Virology, vol. 84, no. 23, pp. 12226–12235, 2010.
View at: Publisher Site | Google Scholar
J. L. Nieva, A. Agirre, S. Nir, and L. Carrasco, “Mechanisms of membrane permeabilization by picornavirus 2B viroporin,” The FEBS Letters, vol. 552, no. 1, pp. 68–73, 2003.
View at: Publisher Site | Google Scholar
F. J. M. van Kuppeveld, A. S. de Jong, W. J. G. Melchers, and P. H. G. M. Willems, “Enterovirus protein 2B po(u)res out the calcium: a viral strategy to survive?” Trends in Microbiology, vol. 13, no. 2, pp. 41–44, 2005.
View at: Publisher Site | Google Scholar
A. S. de Jong, H. J. Visch, F. de Mattia et al., “The coxsackievirus 2B protein increases efflux of ions from the endoplasmic reticulum and Golgi, thereby inhibiting protein trafficking through the Golgi,” The Journal of Biological Chemistry, vol. 281, no. 20, pp. 14144–14150, 2006.
View at: Publisher Site | Google Scholar
A. S. de Jong, F. de Mattia, M. M. van Dommelen et al., “Functional analysis of picornavirus 2B proteins: effects on calcium homeostasis and intracellular protein trafficking,” Journal of Virology, vol. 82, no. 7, pp. 3782–3790, 2008.
View at: Publisher Site | Google Scholar
F. J. M. van Kuppeveld, J. G. J. Hoenderop, R. L. L. Smeets et al., “Coxsackievirus protein 2B modifies endoplasmic reticulum membrane and plasma membrane permeability and facilitates virus release,” EMBO Journal, vol. 16, no. 12, pp. 3519–3532, 1997.
View at: Publisher Site | Google Scholar
M. Campanella, A. S. de Jong, K. W. H. Lanke et al., “The coxsackievirus 2B protein suppresses apoptotic host cell responses by manipulating intracellular Ca²⁺ homeostasis,” The Journal of Biological Chemistry, vol. 279, no. 18, pp. 18440–18450, 2004.
View at: Publisher Site | Google Scholar
P. Bozidis, C. D. Williamson, D. S. Wong, and A. M. Colberg-Poley, “Trafficking of UL37 proteins into mitochondrion-associated membranes during permissive human cytomegalovirus infection,” Journal of Virology, vol. 84, no. 15, pp. 7898–7903, 2010.
View at: Publisher Site | Google Scholar
R. Sharon-Friling, J. Goodhouse, A. M. Colberg-Poley, and T. Shenk, “Human cytomegalovirus pUL37x1 induces the release of endoplasmic reticulum calcium stores,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 50, pp. 19117–19122, 2006.
View at: Publisher Site | Google Scholar
P. Pinton, D. Ferrari, E. Rapizzi, F. Di Virgilio, T. Pozzan, and R. Rizzuto, “The Ca²⁺ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action,” EMBO Journal, vol. 20, no. 11, pp. 2690–2701, 2001.
View at: Publisher Site | Google Scholar
A. R. Moise, J. R. Grant, T. Z. Vitalis, and W. A. Jefferies, “Adenovirus E3-6.7K maintains calcium homeostasis and prevents apoptosis and arachidonic acid release,” Journal of Virology, vol. 76, no. 4, pp. 1578–1587, 2002.
View at: Google Scholar
P. H. Chan, K. Niizuma, and H. Endo, “Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival,” Journal of Neurochemistry, vol. 109, no. 1, pp. 133–138, 2009.
View at: Publisher Site | Google Scholar
F. Muller, A. R. Crofts, and D. M. Kramer, “Multiple Q-cycle bypass reactions at the Qo site of the cytochrome bc1 complex,” Biochemistry, vol. 41, no. 25, pp. 7866–7874, 2002.
View at: Publisher Site | Google Scholar
F. L. Muller, A. G. Roberts, M. K. Bowman, and D. M. Kramer, “Architecture of the Q-o site of the cytochrome bc1 complex probed by superoxide production,” Biochemistry, vol. 42, no. 21, pp. 6493–6499, 2003.
View at: Publisher Site | Google Scholar
F. L. Muller, Y. Liu, and H. van Remmen, “Complex III releases superoxide to both sides of the inner mitochondrial membrane,” The Journal of Biological Chemistry, vol. 279, no. 47, pp. 49064–49073, 2004.
View at: Publisher Site | Google Scholar
V. P. Skulachev, “Bioenergetic aspects of apoptosis, necrosis and mitoptosis,” Apoptosis, vol. 11, no. 4, pp. 473–485, 2006.
View at: Publisher Site | Google Scholar
J. St-Pierre, J. A. Buckingham, S. J. Roebuck, and M. D. Brand, “Topology of superoxide production from different sites in the mitochondrial electron transport chain,” The Journal of Biological Chemistry, vol. 277, no. 47, pp. 44784–44790, 2002.
View at: Publisher Site | Google Scholar
D. Han, F. Antunes, R. Canali, D. Rettori, and E. Cadenas, “Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol,” The Journal of Biological Chemistry, vol. 278, no. 8, pp. 5557–5563, 2003.
View at: Publisher Site | Google Scholar
S. Miwa, J. St-Pierre, L. Partridge, and M. D. Brand, “Superoxide and hydrogen peroxide production by Drosophila mitochondria,” Free Radical Biology and Medicine, vol. 35, no. 8, pp. 938–948, 2003.
View at: Publisher Site | Google Scholar
H. Tsutsui, T. Ide, and S. Kinugawa, “Mitochondrial oxidative stress, DNA damage, and heart failure,” Antioxidants and Redox Signaling, vol. 8, no. 9-10, pp. 1737–1744, 2006.
View at: Publisher Site | Google Scholar
D. F. Stowe and A. K. S. Camara, “Mitochondrial reactive oxygen species production in excitable cells: modulators of mitochondrial and cell function,” Antioxidants and Redox Signaling, vol. 11, no. 6, pp. 1373–1414, 2009.
View at: Publisher Site | Google Scholar
H. Tsutsui, S. Kinugawa, and S. Matsushima, “Mitochondrial oxidative stress and dysfunction in myocardial remodelling,” Cardiovascular Research, vol. 81, no. 3, pp. 449–456, 2009.
View at: Publisher Site | Google Scholar
J. M. Taylor, D. Quilty, L. Banadyga, and M. Barry, “The vaccinia virus protein F1L interacts with Bim and inhibits activation of the pro-apoptotic protein Bax,” The Journal of Biological Chemistry, vol. 281, no. 51, pp. 39728–39739, 2006.
View at: Publisher Site | Google Scholar
M. Ott, J. D. Robertson, V. Gogvadze, B. Zhivotovsky, and S. Orrenius, “Cytochrome c release from mitochondria proceeds by a two-step process,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 3, pp. 1259–1263, 2002.
View at: Publisher Site | Google Scholar
S. Raha, A. T. Myint, L. Johnstone, and B. H. Robinson, “Control of oxygen free radical formation from mitochondrial complex I: roles for protein kinase A and pyruvate dehydrogenase kinase,” Free Radical Biology and Medicine, vol. 32, no. 5, pp. 421–430, 2002.
View at: Publisher Site | Google Scholar
K. A. McGuire, A. U. Barlan, T. M. Griffin, and C. M. Wiethoff, “Adenovirus type 5 rupture of lysosomes leads to cathepsin B-dependent mitochondrial stress and production of reactive oxygen species,” Journal of Virology, vol. 85, no. 20, pp. 10806–10813, 2011.
View at: Publisher Site | Google Scholar
S. Nishina, K. Hino, M. Korenaga et al., “Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription,” Gastroenterology, vol. 134, no. 1, pp. 226–238, 2008.
View at: Publisher Site | Google Scholar
N. S. R. de Mochel, S. Seronello, S. H. Wang et al., “Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis C virus infection,” Hepatology, vol. 52, no. 1, pp. 47–59, 2010.
View at: Publisher Site | Google Scholar
M. J. Hsieh, Y. S. Hsieh, T. Y. Chen, and H. L. Chiou, “Hepatitis C virus E2 protein induce reactive oxygen species (ROS)-related fibrogenesis in the HSC-T6 hepatic stellate cell line,” Journal of Cellular Biochemistry, vol. 112, no. 1, pp. 233–243, 2010.
View at: Publisher Site | Google Scholar
K. Machida, G. Mcnamara, K. T. Cheng et al., “Hepatitis C virus inhibits DNA damage repair through reactive oxygen and nitrogen species and by interfering with the ATM-NBS1/Mre11/Rad50 DNA repair pathway in monocytes and hepatocytes,” Journal of Immunology, vol. 185, no. 11, pp. 6985–6998, 2010.
View at: Publisher Site | Google Scholar
I. I. Kruman, A. Nath, and M. P. Mattson, “HIV-1 protein tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress,” Experimental Neurology, vol. 154, no. 2, pp. 276–288, 1998.
View at: Publisher Site | Google Scholar
M. A. Baugh, “HIV: reactive oxygen species, enveloped viruses and hyperbaric oxygen,” Medical Hypotheses, vol. 55, no. 3, pp. 232–238, 2000.
View at: Publisher Site | Google Scholar
L. Gil, A. Tarinas, D. Hernandez et al., “Altered oxidative stress indexes related to disease progression marker in human immunodeficiency virus infected patients with antiretroviral therapy,” Biomedicine and Aging Pathology, vol. 1, no. 1, pp. 8–15, 2011.
View at: Publisher Site | Google Scholar
C. W. Pyo, Y. L. Yang, N. K. Yoo, and S. Y. Choi, “Reactive oxygen species activate HIV long terminal repeat via post-translational control of NF-κB,” Biochemical and Biophysical Research Communications, vol. 376, no. 1, pp. 180–185, 2008.
View at: Publisher Site | Google Scholar
W. Lin, G. Wu, S. Li et al., “HIV and HCV cooperatively promote hepatic fibrogenesis via induction of reactive oxygen species and NF κB,” The Journal of Biological Chemistry, vol. 286, no. 4, pp. 2665–2674, 2011.
View at: Publisher Site | Google Scholar
S. Lassoued, B. Gargouri, A. E. F. El Feki, H. Attia, and J. van Pelt, “Transcription of the epstein-barr virus lytic cycle activator BZLF-1 during oxidative stress induction,” Biological Trace Element Research, vol. 137, no. 1, pp. 13–22, 2010.
View at: Publisher Site | Google Scholar
S. Lassoued, R. B. Ameur, W. Ayadi, B. Gargouri, R. B. Mansour, and H. Attia, “Epstein-Barr virus induces an oxidative stress during the early stages of infection in B lymphocytes, epithelial, and lymphoblastoid cell lines,” Molecular and Cellular Biochemistry, vol. 313, no. 1-2, pp. 179–186, 2008.
View at: Publisher Site | Google Scholar
B. Gargouri, J. van Pelt, A. E. F. El Feki, H. Attia, and S. Lassoued, “Induction of Epstein-Barr virus (EBV) lytic cycle in vitro causes oxidative stress in lymphoblastoid B cell lines,” Molecular and Cellular Biochemistry, vol. 324, no. 1-2, pp. 55–63, 2009.
View at: Publisher Site | Google Scholar
Y. J. Kim, J. K. Jung, S. Y. Lee, and K. L. Jang, “Hepatitis B virus X protein overcomes stress-induced premature senescence by repressing p16INK4a expression via DNA methylation,” Cancer Letters, vol. 288, no. 2, pp. 226–235, 2010.
View at: Publisher Site | Google Scholar
L. Hu, L. Chen, G. Yang et al., “HBx sensitizes cells to oxidative stress-induced apoptosis by accelerating the loss of Mcl-1 protein via caspase-3 cascade,” Molecular Cancer, vol. 10, article 43, 2011.
View at: Publisher Site | Google Scholar
S. Schaedler, J. Krause, K. Himmelsbach et al., “Hepatitis B virus induces expression of antioxidant response element-regulated genes by activation of Nrf2,” The Journal of Biological Chemistry, vol. 285, no. 52, pp. 41074–41086, 2010.
View at: Publisher Site | Google Scholar
R. Srisuttee, S. S. Koh, E. H. Park et al., “Up-regulation of Foxo4 mediated by hepatitis B virus X protein confers resistance to oxidative stress-induced cell death,” International Journal of Molecular Medicine, vol. 28, no. 2, pp. 255–260, 2011.
View at: Publisher Site | Google Scholar
A. Bhargava, S. Khan, H. Panwar et al., “Occult hepatitis B virus infection with low viremia induces DNA damage, apoptosis and oxidative stress in peripheral blood lymphocytes,” Virus Research, vol. 153, no. 1, pp. 143–150, 2010.
View at: Publisher Site | Google Scholar
Y. Ano, A. Sakudo, T. Kimata, R. Uraki, K. Sugiura, and T. Onodera, “Oxidative damage to neurons caused by the induction of microglial NADPH oxidase in encephalomyocarditis virus infection,” Neuroscience Letters, vol. 469, no. 1, pp. 39–43, 2010.
View at: Publisher Site | Google Scholar
M. Colombini, E. Blachly-Dyson, and M. Forte, “VDAC, a channel in the outer mitochondrial membrane,” Ion channels, vol. 4, pp. 169–202, 1996.
View at: Google Scholar
M. Forte, E. Blachly-Dyson, and M. Colombini, “Structure and function of the yeast outer mitochondrial membrane channel, VDAC,” Society of General Physiologists Series, vol. 51, pp. 145–154, 1996.
View at: Google Scholar
S. Villinger, R. Briones, K. Giller et al., “Functional dynamics in the voltage-dependent anion channel,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 52, pp. 22546–22551, 2010.
View at: Publisher Site | Google Scholar
E. Pebay-Peyroula, C. Dahout-Gonzalez, R. Kahn, V. Trézéguet, G. J. Lauquin, and G. Brandolin, “Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside,” Nature, vol. 426, no. 6962, pp. 39–44, 2003.
View at: Publisher Site | Google Scholar
D. R. Hunter and R. A. Haworth, “The Ca²⁺-induced membrane transition in mitochondria. The protective mechanisms,” Archives of Biochemistry and Biophysics, vol. 195, no. 2, pp. 453–459, 1979.
View at: Google Scholar
K. D. Garlid, X. Sun, P. Paucek, and G. Woldegiorgis, “Mitochondrial cation transport systems,” Methods in Enzymology, vol. 260, pp. 331–348, 1995.
View at: Publisher Site | Google Scholar
P. Bernardi, “Mitochondrial transport of cations: channels, exchangers, and permeability transition,” Physiological Reviews, vol. 79, no. 4, pp. 1127–1155, 1999.
View at: Google Scholar
A. P. Halestrap, “Calcium, mitochondria and reperfusion injury: a pore way to die,” Biochemical Society Transactions, vol. 34, no. 2, pp. 232–237, 2006.
View at: Publisher Site | Google Scholar
K. Szydlowska and M. Tymianski, “Calcium, ischemia and excitotoxicity,” Cell Calcium, vol. 47, no. 2, pp. 122–129, 2010.
View at: Publisher Site | Google Scholar
C. Piccoli, R. Scrima, G. Quarato et al., “Hepatitis C virus protein expression causes calcium-mediated mitochondrial bioenergetic dysfunction and nitro-oxidative stress,” Hepatology, vol. 46, no. 1, pp. 58–65, 2007.
View at: Publisher Site | Google Scholar
M. Gac, J. Bigda, and T. W. Vahlenkamp, “Increased mitochondrial superoxide dismutase expression and lowered production of reactive oxygen species during rotavirus infection,” Virology, vol. 404, no. 2, pp. 293–303, 2010.
View at: Publisher Site | Google Scholar
S. Carrère-Kremer, C. Montpellier-Pala, L. Cocquerel, C. Wychowski, F. Penin, and J. Dubuisson, “Subcellular localization and topology of the p7 polypeptide of hepatitis C virus,” Journal of Virology, vol. 76, no. 8, pp. 3720–3730, 2002.
View at: Publisher Site | Google Scholar
M. E. Gonzalez and L. Carrasco, “Viroporins,” The FEBS Letters, vol. 552, no. 1, pp. 28–34, 2003.
View at: Publisher Site | Google Scholar
D. Pavlovic, D. C. A. Neville, O. Argaud et al., “The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 10, pp. 6104–6108, 2003.
View at: Publisher Site | Google Scholar
A. Azuma, A. Matsuo, T. Suzuki, T. Kurosawa, X. Zhang, and Y. Aida, “Human immunodeficiency virus type 1 Vpr induces cell cycle arrest at the G1 phase and apoptosis via disruption of mitochondrial function in rodent cells,” Microbes and Infection, vol. 8, no. 3, pp. 670–679, 2006.
View at: Publisher Site | Google Scholar
E. Jacotot, L. Ravagnan, M. Loeffler et al., “The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore,” Journal of Experimental Medicine, vol. 191, no. 1, pp. 33–46, 2000.
View at: Publisher Site | Google Scholar
A. Deniaud, C. Brenner, and G. Kroemer, “Mitochondrial membrane permeabilization by HIV-1 Vpr,” Mitochondrion, vol. 4, no. 2-3, pp. 223–233, 2004.
View at: Publisher Site | Google Scholar
A. Macho, M. A. Calzado, L. Jiménez-Reina, E. Ceballos, J. León, and E. Muñoz, “Susceptibility of HIV-1-TAT transfected cells to undergo apoptosis. Biochemical mechanisms,” Oncogene, vol. 18, no. 52, pp. 7543–7551, 1999.
View at: Google Scholar
H. Everett, M. Barry, X. Sun et al., “The myxoma poxvirus protein, M11L, prevents apoptosis by direct interaction with the mitochondrial permeability transition pore,” Journal of Experimental Medicine, vol. 196, no. 9, pp. 1127–1139, 2002.
View at: Publisher Site | Google Scholar
H. Everett, M. Barry, S. F. Lee et al., “M11L: a novel mitochondria-localized protein of myxoma virus that blocks apoptosis of infected leukocytes,” Journal of Experimental Medicine, vol. 191, no. 9, pp. 1487–1498, 2000.
View at: Publisher Site | Google Scholar
J. L. Macen, K. A. Graham, S. F. Lee, M. Schreiber, L. K. Boshkov, and G. McFadden, “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, vol. 218, no. 1, pp. 232–237, 1996.
View at: Publisher Site | Google Scholar
S. T. Wasilenko, T. L. Stewart, A. F. A. Meyers, and M. Barry, “Vaccinia virus encodes a previously uncharacterized mitochondrial-associated inhibitor of apoptosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 2, pp. 14345–14350, 2003.
View at: Publisher Site | Google Scholar
S. T. Wasilenko, L. Banadyga, D. Bond, and M. Barry, “The vaccinia virus F1L protein interacts with the proapoptotic protein Bak and inhibits Bak activation,” Journal of Virology, vol. 79, no. 22, pp. 14031–14043, 2005.
View at: Publisher Site | Google Scholar
S. T. Wasilenko, A. F. A. Meyers, K. V. Helm, and M. Barry, “Vaccinia virus infection disarms the mitochondrion-mediated pathway of the apoptotic cascade by modulating the permeability transition pore,” Journal of Virology, vol. 75, no. 23, pp. 11437–11448, 2001.
View at: Publisher Site | Google Scholar
K. Bruns, N. Studtrucker, A. Sharma et al., “Structural characterization and oligomerization of PB1-F2, a proapoptotic influenza A virus protein,” The Journal of Biological Chemistry, vol. 282, no. 1, pp. 353–363, 2007.
View at: Publisher Site | Google Scholar
W. Chen, P. A. Calvo, D. Malide et al., “A novel influenza A virus mitochondrial protein that induces cell death,” Nature Medicine, vol. 7, no. 12, pp. 1306–1312, 2001.
View at: Publisher Site | Google Scholar
J. S. Gibbs, D. Malide, F. Hornung, J. R. Bennink, and J. W. Yewdell, “The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function,” Journal of Virology, vol. 77, no. 13, pp. 7214–7224, 2003.
View at: Publisher Site | Google Scholar
M. Henkel, D. Mitzner, P. Henklein et al., “Proapoptotic influenza A virus protein PB1-F2 forms a nonselective ion channel,” PLoS ONE, vol. 5, no. 6, Article ID e11112, 2010.
View at: Publisher Site | Google Scholar
M. Danishuddin, S. N. Khan, and A. U. Khan, “Molecular interactions between mitochondrial membrane proteins and the C-terminal domain of PB1-F2: an in silico approach,” Journal of Molecular Modeling, vol. 16, no. 3, pp. 535–541, 2010.
View at: Publisher Site | Google Scholar
M. Silic-Benussi, O. Marin, R. Biasiotto, D. M. D'Agostino, and V. Ciminale, “Effects of human T-cell leukemia virus type 1 (HTLV-1) p13 on mitochondrial K⁺ permeability: a new member of the viroporin family?” The FEBS Letters, vol. 584, no. 10, pp. 2070–2075, 2010.
View at: Publisher Site | Google Scholar
V. Ciminale, L. Zotti, D. M. D'Agostino et al., “Mitochondrial targeting of the p13(II) protein coded by the x-II ORF of human T-cell leukemia/lymphotropic virus type I (HTLV-I),” Oncogene, vol. 18, no. 31, pp. 4505–4514, 1999.
View at: Publisher Site | Google Scholar
R. Biasiotto, P. Aguiari, R. Rizzuto, P. Pinton, D. M. D'Agostino, and V. Ciminale, “The p13 protein of human T cell leukemia virus type 1 (HTLV-1) modulates mitochondrial membrane potential and calcium uptake,” Biochimica et Biophysica Acta, vol. 1797, no. 6-7, pp. 945–951, 2010.
View at: Publisher Site | Google Scholar
M. Silic-Benussi, I. Cavallari, T. Zorzan et al., “Suppression of tumor growth and cell proliferation by p13II, a mitochondrial protein of human T cell leukemia virus type 1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 17, pp. 6629–6634, 2004.
View at: Publisher Site | Google Scholar
W. A. Nudson, J. Rovnak, M. Buechner, and S. L. Quackenbush, “Walleye dermal sarcoma virus Orf C is targeted to the mitochondria,” Journal of General Virology, vol. 84, no. 2, pp. 375–381, 2003.
View at: Publisher Site | Google Scholar
E. White, “Mechanisms of apoptosis regulation by viral oncogenes in infection and tumorigenesis,” Cell Death and Differentiation, vol. 13, no. 8, pp. 1371–1377, 2006.
View at: Publisher Site | Google Scholar
L. Galluzzi, C. Brenner, E. Morselli, Z. Touat, and G. Kroemer, “Viral control of mitochondrial apoptosis,” PLoS Pathogens, vol. 4, no. 5, Article ID e1000018, 2008.
View at: Publisher Site | Google Scholar
C. A. Benedict, P. S. Norris, and C. F. Ware, “To kill or be killed: viral evasion of apoptosis,” Nature Immunology, vol. 3, no. 11, pp. 1013–1018, 2002.
View at: Publisher Site | Google Scholar
S. Hay and G. Kannourakis, “A time to kill: viral manipulation of the cell death program,” Journal of General Virology, vol. 83, no. 7, pp. 1547–1564, 2002.
View at: Google Scholar
J. F. Kerr, A. H. Wyllie, and A. R. Currie, “Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics,” The British Journal of Cancer, vol. 26, no. 4, pp. 239–257, 1972.
View at: Google Scholar
E. Gulbins, S. Dreschers, and J. Bock, “Role of mitochondria in apoptosis,” Experimental Physiology, vol. 88, no. 1, pp. 85–90, 2003.
View at: Publisher Site | Google Scholar
V. Borutaite, “Mitochondria as decision-makers in cell death,” Environmental and Molecular Mutagenesis, vol. 51, no. 5, pp. 406–416, 2010.
View at: Publisher Site | Google Scholar
C. M. Sanfilippo and J. A. Blaho, “The facts of death,” International Reviews of Immunology, vol. 22, no. 5-6, pp. 327–340, 2003.
View at: Publisher Site | Google Scholar
X. Liu, C. N. Kim, J. Yang, R. Jemmerson, and X. Wang, “Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c,” Cell, vol. 86, no. 1, pp. 147–157, 1996.
View at: Publisher Site | Google Scholar
C. Castanier and D. Arnoult, “Mitochondrial dynamics during apoptosis,” Medecine/Sciences, vol. 26, no. 10, pp. 830–835, 2010.
View at: Google Scholar
H. Zou, W. J. Henzel, X. Liu, A. Lutschg, and X. Wang, “Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3,” Cell, vol. 90, no. 3, pp. 405–413, 1997.
View at: Publisher Site | Google Scholar
M. Karbowski, “Mitochondria on guard: role of mitochondrial fusion and fission in the regulation of apoptosis,” Advances in Experimental Medicine and Biology, vol. 687, pp. 131–142, 2010.
View at: Publisher Site | Google Scholar
X. M. Sun, M. MacFarlane, J. Zhuang, B. B. Wolf, D. R. Green, and G. M. Cohen, “Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis,” The Journal of Biological Chemistry, vol. 274, no. 8, pp. 5053–5060, 1999.
View at: Publisher Site | Google Scholar
A. Ashkenazi and V. M. Dixit, “Death receptors: signaling and modulation,” Science, vol. 281, no. 5381, pp. 1305–1308, 1998.
View at: Google Scholar
K. F. Ferri and G. Kroemer, “Organelle-specific initiation of cell death pathways,” Nature Cell Biology, vol. 3, no. 11, pp. E255–E263, 2001.
View at: Publisher Site | Google Scholar
L. Ravagnan, T. Roumier, and G. Kroemer, “Mitochondria, the killer organelles and their weapons,” Journal of Cellular Physiology, vol. 192, no. 2, pp. 131–137, 2002.
View at: Publisher Site | Google Scholar
S. Ohta, “A multi-functional organelle mitochondrion is involved in cell death, proliferation and disease,” Current Medicinal Chemistry, vol. 10, no. 23, pp. 2485–2494, 2003.
View at: Publisher Site | Google Scholar
N. N. Danial, A. Gimenez-Cassina, and D. Tondera, “Homeostatic functions of BCL-2 proteins beyond apoptosis,” Advances in Experimental Medicine and Biology, vol. 687, pp. 1–32, 2010.
View at: Publisher Site | Google Scholar
M. E. Soriano and L. Scorrano, “The interplay between BCL-2 family proteins and mitochondrial morphology in the regulation of apoptosis,” Advances in Experimental Medicine and Biology, vol. 687, pp. 97–114, 2010.
View at: Publisher Site | Google Scholar
S. Krishna, I. C. C. Low, and S. Pervaiz, “Regulation of mitochondrial metabolism: yet another facet in the biology of the oncoprotein Bcl-2,” Biochemical Journal, vol. 435, no. 3, pp. 545–551, 2011.
View at: Publisher Site | Google Scholar
F. Llambi and D. R. Green, “Apoptosis and oncogenesis: give and take in the BCL-2 family,” Current Opinion in Genetics and Development, vol. 21, no. 1, pp. 12–20, 2011.
View at: Publisher Site | Google Scholar
L. Scorrano and S. J. Korsmeyer, “Mechanisms of cytochrome c release by proapoptotic BCL-2 family members,” Biochemical and Biophysical Research Communications, vol. 304, no. 3, pp. 437–444, 2003.
View at: Publisher Site | Google Scholar
M. Crompton, “Bax, Bid and the permeabilization of the mitochondrial outer membrane in apoptosis,” Current Opinion in Cell Biology, vol. 12, no. 4, pp. 414–419, 2000.
View at: Publisher Site | Google Scholar
N. J. Waterhouse, J. E. Ricci, and D. R. Green, “And all of a sudden it's over: mitochondrial outer-membrane permeabilization in apoptosis,” Biochimie, vol. 84, no. 2-3, pp. 113–121, 2002.
View at: Publisher Site | Google Scholar
A. S. Belzacq, H. L. A. Vieira, F. Verrier et al., “Bcl-2 and Bax modulate adenine nucleotide translocase activity,” Cancer Research, vol. 63, no. 2, pp. 541–546, 2003.
View at: Google Scholar
N. Zamzami and G. Kroemer, “Apoptosis: mitochondrial membrane permeabilization—the (w)hole story?” Current Biology, vol. 13, no. 2, pp. R71–R73, 2003.
View at: Publisher Site | Google Scholar
G. Paradies, G. Petrosillo, V. Paradies, and F. M. Ruggiero, “Role of cardiolipin peroxidation and Ca²⁺ in mitochondrial dysfunction and disease,” Cell Calcium, vol. 45, no. 6, pp. 643–650, 2009.
View at: Publisher Site | Google Scholar
A. Cuconati and E. White, “Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection,” Genes and Development, vol. 16, no. 19, pp. 2465–2478, 2002.
View at: Publisher Site | Google Scholar
B. J. Thomson, “Viruses and apoptosis,” International Journal of Experimental Pathology, vol. 82, no. 2, pp. 65–76, 2001.
View at: Publisher Site | Google Scholar
D. Perez and E. White, “TNF-α signals apoptosis through a bid-dependent conformational change in Bax that is inhibited by E1B 19K,” Molecular Cell, vol. 6, no. 1, pp. 53–63, 2000.
View at: Google Scholar
B. M. Pützer, T. Stiewe, K. Parssanedjad, S. Rega, and H. Esche, “E1A is sufficient by itself to induce apoptosis independent of p53 and other adenoviral gene products,” Cell Death and Differentiation, vol. 7, no. 2, pp. 177–188, 2000.
View at: Google Scholar
L. Banadyga, J. Gerig, T. Stewart, and M. Barry, “Fowlpox virus encodes a Bcl-2 homologue that protects cells from apoptotic death through interaction with the proapoptotic protein bak,” Journal of Virology, vol. 81, no. 20, pp. 11032–11045, 2007.
View at: Publisher Site | Google Scholar
A. Brun, C. Rivas, M. Esteban, J. M. Escribano, and C. Alonso, “African swine fever virus gene A179L, a viral homologue of bcl-2, protects cells from programmed cell death,” Virology, vol. 225, no. 1, pp. 227–230, 1996.
View at: Publisher Site | Google Scholar
Y. Revilla, A. Cebrián, E. Baixerás, C. Martínez, E. Viñuela, and M. L. Salas, “Inhibition of apoptosis by the African swine fever virus Bcl-2 homologue: role of the BH1 domain,” Virology, vol. 228, no. 2, pp. 400–404, 1997.
View at: Publisher Site | Google Scholar
T. Derfuss, H. Fickenscher, M. S. Kraft et al., “Antiapoptotic activity of the herpesvirus saimiri-encoded Bcl-2 homolog: stabilization of mitochondria and inhibition of caspase-3-like activity,” Journal of Virology, vol. 72, no. 7, pp. 5897–5904, 1998.
View at: Google Scholar
W. L. Marshall, C. Yim, E. Gustafson et al., “Epstein-Barr virus encodes a novel homolog of the bcl-2 oncogene that inhibits apoptosis and associates with Bax and Bak,” Journal of Virology, vol. 73, no. 6, pp. 5181–5185, 1999.
View at: Google Scholar
X. M. Yin, Z. N. Oltvai, and S. J. Korsmeyer, “BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax,” Nature, vol. 369, no. 6478, pp. 321–323, 1994.
View at: Publisher Site | Google Scholar
Z. Rahmani, K. W. Huh, R. Lasher, and A. Siddiqui, “Hepatitis B virus X protein colocalizes to mitochondria with a human voltage-dependent anion channel, HVDAC3, and alters its transmembrane potential,” Journal of Virology, vol. 74, no. 6, pp. 2840–2846, 2000.
View at: Publisher Site | Google Scholar
Y. W. Lu and W. N. Chen, “Human hepatitis B virus X protein induces apoptosis in HepG2 cells: role of BH3 domain,” Biochemical and Biophysical Research Communications, vol. 338, no. 3, pp. 1551–1556, 2005.
View at: Publisher Site | Google Scholar
Y. Tanaka, F. Kanai, T. Kawakami 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, vol. 318, no. 2, pp. 461–469, 2004.
View at: Publisher Site | Google Scholar
J. Diao, A. A. Khine, F. Sarangi et al., “X protein of hepatitis B virus inhibits Fas-mediated apoptosis and is associated with up-regulation of the SAPK/JNK pathway,” The Journal of Biological Chemistry, vol. 276, no. 11, pp. 8328–8340, 2001.
View at: Publisher Site | Google Scholar
A. S. Kekule, U. Lauer, L. Weiss, B. Luber, and P. H. Hofschneider, “Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway,” Nature, vol. 361, no. 6414, pp. 742–745, 1993.
View at: Publisher Site | Google Scholar
F. Su and R. J. Schneider, “Hepatitis B virus HBx protein activates transcription factor NF-κB by acting on multiple cytoplasmic inhibitors of rel-related proteins,” Journal of Virology, vol. 70, no. 7, pp. 4558–4566, 1996.
View at: Google Scholar
J. Benn, F. Su, M. Doria, and R. J. Schneider, “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,” Journal of Virology, vol. 70, no. 8, pp. 4978–4985, 1996.
View at: Google Scholar
F. Henkler, A. R. Lopes, M. Jones, and R. Koshy, “Erk-independent partial activation of AP-1 sites by the hepatitis B virus HBx protein,” Journal of General Virology, vol. 79, no. 11, pp. 2737–2742, 1998.
View at: Google Scholar
W. L. Shih, M. L. Kuo, S. E. Chuang, A. L. Cheng, and S. L. Doong, “Hepatitis b virus x protein inhibits transforming growth factor-β-induced apoptosis through the activation of phosphatidylinositol 3-kinase pathway,” The Journal of Biological Chemistry, vol. 275, no. 33, pp. 25858–25864, 2000.
View at: Publisher Site | Google Scholar
J. Komano, M. Sugiura, and K. Takada, “Epstein-barr virus contributes to the malignant phenotype and to apoptosis resistance in Burkitt's lymphoma cell line Akata,” Journal of Virology, vol. 72, no. 11, pp. 9150–9156, 1998.
View at: Google Scholar
D. S. Bellows, M. Howell, C. Pearson, S. A. Hazlewood, and J. M. Hardwick, “Epstein-Barr virus BALF1 is a BCL-2-like antagonist of the herpesvirus antiapoptotic BCL-2 proteins,” Journal of Virology, vol. 76, no. 5, pp. 2469–2479, 2002.
View at: Publisher Site | Google Scholar
A. M. Flanagan and A. Letai, “BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2,” Cell Death and Differentiation, vol. 15, no. 3, pp. 580–588, 2008.
View at: Publisher Site | Google Scholar
M. Thomas and L. Banks, “Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types,” Journal of General Virology, vol. 80, no. 6, pp. 1513–1517, 1999.
View at: Google Scholar
S. Jackson, C. Harwood, M. Thomas, L. Banks, and A. Storey, “Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins,” Genes and Development, vol. 14, no. 23, pp. 3065–3073, 2000.
View at: Publisher Site | Google Scholar
S. Leverrier, D. Bergamaschi, L. Ghali et al., “Role of HPV E6 proteins in preventing UVB-induced release of pro-apoptotic factors from the mitochondria,” Apoptosis, vol. 12, no. 3, pp. 549–560, 2007.
View at: Publisher Site | Google Scholar
Z. M. Sun, Y. Xiao, L. L. Ren, X. B. Lei, and J. W. Wang, “Enterovirus 71 induces apoptosis in a Bax dependent manner,” Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi, vol. 25, no. 1, pp. 49–52, 2011.
View at: Google Scholar
C. S. Ilkow, I. S. Goping, and T. C. Hobman, “The rubella virus capsid is an anti-apoptotic protein that attenuates the pore-forming ability of Bax,” PLoS Pathogens, vol. 7, no. 2, Article ID e1001291, 2011.
View at: Publisher Site | Google Scholar
V. S. Goldmacher, L. M. Bartle, A. Skaletskaya et al., “A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 22, pp. 12536–12541, 1999.
View at: Publisher Site | Google Scholar
D. Arnoult, L. M. Bartle, A. Skaletskaya et al., “Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 21, pp. 7988–7993, 2004.
View at: Publisher Site | Google Scholar
D. Poncet, N. Larochette, A. Pauleau et al., “An anti-apoptotic viral protein that recruits Bax to mitochondria,” The Journal of Biological Chemistry, vol. 279, no. 21, pp. 22605–22614, 2004.
View at: Publisher Site | Google Scholar
H. L. A. Vieira, A. S. Belzacq, D. Haouzi et al., “The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal,” Oncogene, vol. 20, no. 32, pp. 4305–4316, 2001.
View at: Publisher Site | Google Scholar
P. Boya, M. C. Morales, R. Gonzalez-Polo et al., “The chemopreventive agent N-(4-hydroxyphenyl)retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl-2 family,” Oncogene, vol. 22, no. 40, pp. 6220–6230, 2003.
View at: Publisher Site | Google Scholar
A. L. McCormick, V. L. Smith, D. Chow, and E. S. Mocarski, “Disruption of mitochondrial networks by the human cytomegalovirus UL37 gene product viral mitochondrion-localized inhibitor of apoptosis,” Journal of Virology, vol. 77, no. 1, pp. 631–641, 2003.
View at: Publisher Site | Google Scholar
M. G. Katze, Y. He, and M. Gale Jr., “Viruses and interferon: a fight for supremacy,” Nature Reviews Immunology, vol. 2, no. 9, pp. 675–687, 2002.
View at: Publisher Site | Google Scholar
M. Yoneyama, M. Kikuchi, T. Natsukawa et al., “The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses,” Nature Immunology, vol. 5, no. 7, pp. 730–737, 2004.
View at: Publisher Site | Google Scholar
J. Andrejeva, K. S. Childs, D. F. Young et al., “The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-β promoter,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 49, pp. 17264–17269, 2004.
View at: Publisher Site | Google Scholar
T. Maniatis, J. V. Falvo, T. H. Kim et al., “Structure and function of the interferon-β enhanceosome,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 63, pp. 609–620, 1998.
View at: Google Scholar
I. Scott, “The role of mitochondria in the mammalian antiviral defense system,” Mitochondrion, vol. 10, no. 4, pp. 316–320, 2010.
View at: Publisher Site | Google Scholar
C. Castanier and D. Arnoult, “Mitochondrial localization of viral proteins as a means to subvert host defense,” Biochimica et Biophysica Acta, vol. 1813, no. 4, pp. 575–583, 2011.
View at: Publisher Site | Google Scholar
C. Wang, X. Liu, and B. Wei, “Mitochondrion: an emerging platform critical for host antiviral signaling,” Expert Opinion on Therapeutic Targets, vol. 15, no. 5, pp. 647–665, 2011.
View at: Publisher Site | Google Scholar
R. B. Seth, L. Sun, and Z. J. Chen, “Antiviral innate immunity pathways,” Cell Research, vol. 16, no. 2, pp. 141–147, 2006.
View at: Publisher Site | Google Scholar
L. G. Xu, Y. Y. Wang, K. J. Han, L. Y. Li, Z. Zhai, and H. B. Shu, “VISA is an adapter protein required for virus-triggered IFN-β signaling,” Molecular Cell, vol. 19, no. 6, pp. 727–740, 2005.
View at: Publisher Site | Google Scholar
T. Kawai, K. Takahashi, S. Sato et al., “IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction,” Nature Immunology, vol. 6, no. 10, pp. 981–988, 2005.
View at: Publisher Site | Google Scholar
E. Meylan, J. Curran, K. Hofmann et al., “Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus,” Nature, vol. 437, no. 7062, pp. 1167–1172, 2005.
View at: Publisher Site | Google Scholar
Y. Xu, H. Zhong, and W. Shi, “MAVS protects cells from apoptosis by negatively regulating VDAC1,” Molecular and Cellular Biochemistry, vol. 375, no. 1-2, p. 219, 2010.
View at: Publisher Site | Google Scholar
X. D. Li, L. Sun, R. B. Seth, G. Pineda, and Z. J. Chen, “Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 49, pp. 17717–17722, 2005.
View at: Publisher Site | Google Scholar
E. Foy, K. Li, C. Wang et al., “Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease,” Science, vol. 300, no. 5622, pp. 1145–1148, 2003.
View at: Publisher Site | Google Scholar
A. Breiman, N. Grandvaux, R. Lin et al., “Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKε,” Journal of Virology, vol. 79, no. 7, pp. 3969–3978, 2005.
View at: Publisher Site | Google Scholar
E. Foy, K. Li, R. Sumpter Jr. et al., “Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 8, pp. 2986–2991, 2005.
View at: Publisher Site | Google Scholar
B. Beames, D. Chavez, and R. E. Lanford, “GB virus B as a model for hepatitis C virus,” ILAR Journal, vol. 42, no. 2, pp. 152–160, 2001.
View at: Google Scholar
Z. Chen, Y. Benureau, R. Rijnbrand et al., “GB virus B disrupts RIG-I signaling by NS3/4A-mediated cleavage of the adaptor protein MAVS,” Journal of Virology, vol. 81, no. 2, pp. 964–976, 2007.
View at: Publisher Site | Google Scholar
T. Öhman, J. Rintahaka, N. Kalkkinen, S. Matikainen, and T. A. Nyman, “Actin and RIG-I/MAVS signaling components translocate to mitochondria upon influenza a virus infection of human primary macrophages,” Journal of Immunology, vol. 182, no. 9, pp. 5682–5692, 2009.
View at: Publisher Site | Google Scholar
D. A. Matthews and W. C. Russell, “Adenovirus core protein V interacts with p32—a protein which is associated with both the mitochondria and the nucleus,” Journal of General Virology, vol. 79, no. 7, pp. 1677–1685, 1998.
View at: Google Scholar
S. Cen, A. Khorchid, H. Javanbakht et al., “Incorporation of lysyl-tRNA synthetase into human immunodeficiency virus type 1,” Journal of Virology, vol. 75, no. 11, pp. 5043–5048, 2001.
View at: Publisher Site | Google Scholar
E. Tolkunova, H. Park, J. Xia, M. P. King, and E. Davidson, “The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual: alternative splicing of the primary transcript,” The Journal of Biological Chemistry, vol. 275, no. 45, pp. 35063–35069, 2000.
View at: Publisher Site | Google Scholar
M. Kaminska, V. Shalak, M. Francin, and M. Mirande, “Viral hijacking of mitochondrial lysyl-tRNA synthetase,” Journal of Virology, vol. 81, no. 1, pp. 68–73, 2007.
View at: Publisher Site | Google Scholar
L. A. Stark and R. T. Hay, “Human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) interacts with Lys-tRNA synthetase: implications for priming of HIV-1 reverse transcription,” Journal of Virology, vol. 72, no. 4, pp. 3037–3044, 1998.
View at: Google Scholar
L. Q. Qiu, P. Cresswell, and K. C. Chin, “Viperin is required for optimal Th2 responses and T-cell receptor-mediated activation of NF-κB and AP-1,” Blood, vol. 113, no. 15, pp. 3520–3529, 2009.
View at: Publisher Site | Google Scholar
X. Wang, E. R. Hinson, and P. Cresswell, “The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts,” Cell Host and Microbe, vol. 2, no. 2, pp. 96–105, 2007.
View at: Publisher Site | Google Scholar
J. Y. Seo, R. Yaneva, E. R. Hinson, and P. Cresswell, “Human cytomegalovirus directly induces the antiviral protein viperin to enhance infectivity,” Science, vol. 332, no. 6033, pp. 1093–1097, 2011.
View at: Publisher Site | Google Scholar
S. Kim, H. Y. Kim, S. Lee et al., “Hepatitis B virus X protein induces perinuclear mitochondrial clustering in microtubule- and dynein-dependent manners,” Journal of Virology, vol. 81, no. 4, pp. 1714–1726, 2007.
View at: Publisher Site | Google Scholar
Y. Nomura-Takigawa, M. Nagano-Fujii, L. Deng et al., “Non-structural protein 4A of Hepatitis C virus accumulates on mitochondria and renders the cells prone to undergoing mitochondria-mediated apoptosis,” Journal of General Virology, vol. 87, no. 7, pp. 1935–1945, 2006.
View at: Publisher Site | Google Scholar
J. S. Radovanović, V. Todorović, I. Boričić, M. Janković-Hladni, and A. Korać, “Comparative ultrastructural studies on mitochondrial pathology in the liver of AIDS patients: clusters of mitochondria, protuberances, “minimitochondria,” vacuoles, and virus-like particles,” Ultrastructural Pathology, vol. 23, no. 1, pp. 19–24, 1999.
View at: Google Scholar
G. Rojo, M. Chamorro, M. L. Salas, E. Vinuela, J. M. Cuezva, and J. Salas, “Migration of mitochondria to viral assembly sites in African swine fever virus-infected cells,” Journal of Virology, vol. 72, no. 9, pp. 7583–7588, 1998.
View at: Google Scholar
D. C. Kelly, “Frog virus 3 replication: electron microscope observations on the sequence of infection in chick embryo fibroblasts,” Journal of General Virology, vol. 26, no. 1, pp. 71–86, 1975.
View at: Google Scholar
R. S. Fujinami and M. B. A. Oldstone, “Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity,” Science, vol. 230, no. 4729, pp. 1043–1045, 1985.
View at: Google Scholar
A. P. Kohm, K. G. Fuller, and S. D. Miller, “Mimicking the way to autoimmunity: an evolving theory of sequence and structural homology,” Trends in Microbiology, vol. 11, no. 3, pp. 101–105, 2003.
View at: Publisher Site | Google Scholar
M. Monné, A. J. Robinson, C. Boes, M. E. Harbour, I. M. Fearnley, and E. R. S. Kunji, “The mimivirus genome encodes a mitochondrial carrier that transports dATP and dTTP,” Journal of Virology, vol. 81, no. 7, pp. 3181–3186, 2007.
View at: Publisher Site | Google Scholar
H. A. Saffran, J. M. Pare, J. A. Corcoran, S. K. Weller, and J. R. Smiley, “Herpes simplex virus eliminates host mitochondrial DNA,” EMBO Reports, vol. 8, no. 2, pp. 188–193, 2007.
View at: Publisher Site | Google Scholar
J. A. Corcoran, H. A. Saffran, B. A. Duguay, and J. R. Smiley, “Herpes simplex virus UL12.5 targets mitochondria through a mitochondrial localization sequence proximal to the N terminus,” Journal of Virology, vol. 83, no. 6, pp. 2601–2610, 2009.
View at: Publisher Site | Google Scholar
A. Wiedmer, P. Wang, J. Zhou et al., “Epstein-Barr virus immediate-early protein Zta co-opts mitochondrial single-stranded DNA binding protein to promote viral and inhibit mitochondrial DNA replication,” Journal of Virology, vol. 82, no. 9, pp. 4647–4655, 2008.
View at: Publisher Site | Google Scholar
K. Machida, K. T. Cheng, C. K. Lai, K. S. Jeng, V. M. Sung, and M. M. C. Lai, “Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STATS activation,” Journal of Virology, vol. 80, no. 14, pp. 7199–7207, 2006.
View at: Publisher Site | Google Scholar
C. de Mendoza, L. Martin-Carbonero, P. Barreiro et al., “Mitochondrial DNA depletion in HIV-infected patients with chronic hepatitis C and effect of pegylated interferon plus ribavirin therapy,” AIDS, vol. 21, no. 5, pp. 583–588, 2007.
View at: Publisher Site | Google Scholar

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Copyright © 2013 Sanjeev K. Anand and Suresh K. Tikoo. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Advances in Virology

Viruses as Modulators of Mitochondrial Functions

Abstract

1. Introduction

1.1. Mitochondria

1.2. Viruses

2. Viruses Regulate Ca2+ Homeostasis in Host Cells

2.1. Ca2+ Homeostasis

2.2. Regulation by Viruses

3. Viruses Cause Oxidative Stress in Host Cells

3.1. Electron Transport Chain

3.2. Viruses Induce Reactive Oxygen Species

4. Viruses Regulate Mitochondrial Membrane Potential in Host Cells

4.1. Mitochondrial Membrane Potential

4.2. Regulation by Viruses

5. Viruses Regulate Apoptosis

5.1. Apoptosis

5.2. Regulation by Viruses

6. Viruses Modulate Mitochondrial Antiviral Immunity

6.1. Mitochondrial Antiviral Immunity

6.2. Regulation by Viruses

7. Viruses Hijack Host Mitochondrial Proteins

8. Viruses Alter Intracellular Distribution of Mitochondria

9. Viruses Mimic the Host Mitochondrial Proteins

10. Viruses Cause Host Mitochondrial DNA Depletion

11. Conclusions

Acknowledgments

References

Copyright

2. Viruses Regulate Ca²⁺ Homeostasis in Host Cells

2.1. Ca²⁺ Homeostasis