**2. Mitochondrial functions**

Mitochondria are multifunctional organelles that are covered by an outer membrane (OM), within which lie the intermembrane space (IMS) and the inner membrane (IM). The IM is folded into special structures called cristae, so its surface area is much greater than that of the OM. The cristae function as matrices for protein complexes required for the electron transport chain (ETC), and they contain many integral membrane proteins, including adenine nucleotide translocator (ANT) and ATP synthase. The IM remains almost entirely impermeable under normal physiological conditions, thereby allowing the respiratory chain to create an electrochemical gradient. This electric potential is important for maintaining the mitochondrial membrane potential (MMP, Δψm) of the IM. The pumping of protons by the ETC out of the IM activates ATP synthase, which phosphorylates ADP to ATP. The ATP generated on the matrix side of the IM is then exported by ANT in exchange for ADP. The OM has many voltagedependent anion channels (VDACs), which maintains permeability of solutes up to 5000 Da in size under normal physiological conditions. The IMS is chemically equivalent to the cytosol in terms of low molecular weight solutes and has its own special set of proteins. The human mitochondrial genome (about 16,500 bp), which is in the matrix (within the IM), only codes for 13 subunits of the respiratory chain. More than 99% of mitochondrial proteins are encoded by the nuclear genome and then selectively imported into one of the mitochondrial compartments. Thus, the mitochondrial OM, IM, IMS, and matrix have highly unique protein compositions.

proteins from the IMS, such as Cyt C and Smac/DIABLO, as well as caspase independent death effectors, such as apoptosis-inducing factor (AIF) and endonuclease G (EndoG) [9], which have important roles in caspase-independent and caspase-dependent cell death [9]. The MMP (Δψm) transition occurs during the pathogenesis of exogenous factors (e.g., viral proteins, toxins, and prooxidants [9, 10]). A prolonged loss of the MMP (Δψm) leads to serious cell damage, from which the cell cannot recover. Therefore, in the intrinsic pathway of apoptosis, any viral factor that influences the MMP (Δψm) has a major impact on cell fate, either by

In recent years, there has been an increasing focus on the role of the MMP (Δψm) in disease and health. Thus, several recent models based on *in vivo* and *in vitro* studies explain the mechanisms underlying the maintenance and loss of the MMP. A loss of the MMP by any mechanism leads to functional and structural collapse of the mitochondria and cell death [27]. A recent study for first time has shown that dengue virus (DV) infection of human hepatoma cell line (HepG2) leads alteration in the bioenergetic function of mitochondrial morphology leading to MMP loss [28]. The alteration in respiratory properties of HepG2 cells in DV infection results due to decrease in respiratory control ratio (PCR) and ADP/O ratio, which suggest significant alteration in mitochondrial morphology. Another additional feature observed by an increase in proton leak termed mitochondrial uncoupling which occurs by leaking of

MMP loss. Thus, creating an imbalance in ATP synthesis ultimately affects the bioenergetic functions of cell. The biochemical mitochondrial damage induced in cell infected with HCV showed that E1 Protein together with core and NS3 are responsible for ROS production. Core and NS3 induce NO production which causes MMP loss by opening of transition pore [29].

anion (ONOO–), which irreversibly inhibits multiple respiratory complexes (complexes I, II and IV) and aconitase, and activate proton leak and permeability transition pore [30, 31]. Therefore, interfering with energy metabolism by disrupting the ATP synthesis of cell results

Mitochondria undergo a number of processes, such as fusion and fission, in normally functioning healthy cells. However, when mitochondria develop abnormalities, the cell can destroy it by the process of mitophagy [32]. Cells typically eliminate unhealthy mitochondria by mitochondrial fission; they typically use mitochondrial fusion to recycle matrix metabolites, including mtDNA and mitochondrial membranes, for the assembly of new and healthy mitochondria. Therefore, these three processes—mitophagy, fission, and fusion—are interlinked, and they all play prominent roles in maintaining healthy cells [33]. Mitophagy plays an important role in maintaining mitochondrial homeostasis, but can also eliminate healthy mitochondria in cases such as cell starvation, viral invasion, and erythroid cell differentiation [34, 35]. The mitochondrial fusion and fission are highly dynamic. Viruses interfere with these processes to distort mitochondrial dynamic to facilitate their proliferation. Thus, interfering with these processes promotes the interference of different cellular signaling pathways [36–38]. New castal virus

ATP synthase from inner membrane into matrix resulting in decrease in

−

) to form strong peroxynitrite

Modulation of Mitochondria During Viral Infections http://dx.doi.org/10.5772/intechopen.73036 447

inducing or by blocking cell death [9].

F1

in modulation of mitochondrial function.

NO could also interact with another free radical superoxide (O2

**2.2. Effects of viral infections on mitochondrial processes**

protons through Fo

Mitochondria act "powerhouse" of the cell and have several other important functions. The numerous functions of mitochondria make them indispensable to the cell, so when a virus "hijacks" mitochondrial function, it allows it to control the whole cell. Mitochondria have important roles in several signal transduction pathways [18, 19], the process of aging [20], regulation of different biochemical pathways related to cell metabolism [21, 22], PCD [23, 24], development [25, 26], the pathogenesis of numerous diseases immune responses [19], and cell cycle control [19, 27]. The circular mitochondrial genome encodes 13 polypeptides, 2 rRNAs, and 22 tRNAs. All of these mtDNA products are essential for function of the ETC and the generation of ATP by oxidative phosphorylation [9, 27], although many proteins from the nuclear genome are also required. Thus, any injury to mtDNA can affect the whole cell. The mtDNA is more susceptible to damage from ROS because it lacks protective histones, the mitochondrion has more limited DNA repair enzymes, and it is close to ETC, the main center of ATP and ROS production. The matrix of IMS, which contains cytochrome c oxidase (Cyt C, encoded by mtDNA), SMAC/DIABLO (encoded by nuclear DNA), and endonuclease G (encoded by nuclear DNA), acts as a buffer zone between the IM and OM. This matrix region contains many of the enzymes needed for aerobic respiration, dissolved oxygen, water, carbon dioxide, and recyclable intermediates that serve as energy shuttles and have other functions.

#### **2.1. Loss of mitochondrial membrane potential**

A loss of the MMP (Δψm) leads to imbalances in the membrane potentials of the IM and OM, and then to arrest of normal cellular biosynthetic function and bioenergetics, and finally to a "crisis" within the cell. A loss of the MMP (Δψm) also leads to release of several proapoptotic proteins from the IMS, such as Cyt C and Smac/DIABLO, as well as caspase independent death effectors, such as apoptosis-inducing factor (AIF) and endonuclease G (EndoG) [9], which have important roles in caspase-independent and caspase-dependent cell death [9]. The MMP (Δψm) transition occurs during the pathogenesis of exogenous factors (e.g., viral proteins, toxins, and prooxidants [9, 10]). A prolonged loss of the MMP (Δψm) leads to serious cell damage, from which the cell cannot recover. Therefore, in the intrinsic pathway of apoptosis, any viral factor that influences the MMP (Δψm) has a major impact on cell fate, either by inducing or by blocking cell death [9].

In recent years, there has been an increasing focus on the role of the MMP (Δψm) in disease and health. Thus, several recent models based on *in vivo* and *in vitro* studies explain the mechanisms underlying the maintenance and loss of the MMP. A loss of the MMP by any mechanism leads to functional and structural collapse of the mitochondria and cell death [27]. A recent study for first time has shown that dengue virus (DV) infection of human hepatoma cell line (HepG2) leads alteration in the bioenergetic function of mitochondrial morphology leading to MMP loss [28]. The alteration in respiratory properties of HepG2 cells in DV infection results due to decrease in respiratory control ratio (PCR) and ADP/O ratio, which suggest significant alteration in mitochondrial morphology. Another additional feature observed by an increase in proton leak termed mitochondrial uncoupling which occurs by leaking of protons through Fo F1 ATP synthase from inner membrane into matrix resulting in decrease in MMP loss. Thus, creating an imbalance in ATP synthesis ultimately affects the bioenergetic functions of cell. The biochemical mitochondrial damage induced in cell infected with HCV showed that E1 Protein together with core and NS3 are responsible for ROS production. Core and NS3 induce NO production which causes MMP loss by opening of transition pore [29]. NO could also interact with another free radical superoxide (O2 − ) to form strong peroxynitrite anion (ONOO–), which irreversibly inhibits multiple respiratory complexes (complexes I, II and IV) and aconitase, and activate proton leak and permeability transition pore [30, 31]. Therefore, interfering with energy metabolism by disrupting the ATP synthesis of cell results in modulation of mitochondrial function.

#### **2.2. Effects of viral infections on mitochondrial processes**

**2. Mitochondrial functions**

446 Mitochondrial Diseases

**2.1. Loss of mitochondrial membrane potential**

Mitochondria are multifunctional organelles that are covered by an outer membrane (OM), within which lie the intermembrane space (IMS) and the inner membrane (IM). The IM is folded into special structures called cristae, so its surface area is much greater than that of the OM. The cristae function as matrices for protein complexes required for the electron transport chain (ETC), and they contain many integral membrane proteins, including adenine nucleotide translocator (ANT) and ATP synthase. The IM remains almost entirely impermeable under normal physiological conditions, thereby allowing the respiratory chain to create an electrochemical gradient. This electric potential is important for maintaining the mitochondrial membrane potential (MMP, Δψm) of the IM. The pumping of protons by the ETC out of the IM activates ATP synthase, which phosphorylates ADP to ATP. The ATP generated on the matrix side of the IM is then exported by ANT in exchange for ADP. The OM has many voltagedependent anion channels (VDACs), which maintains permeability of solutes up to 5000 Da in size under normal physiological conditions. The IMS is chemically equivalent to the cytosol in terms of low molecular weight solutes and has its own special set of proteins. The human mitochondrial genome (about 16,500 bp), which is in the matrix (within the IM), only codes for 13 subunits of the respiratory chain. More than 99% of mitochondrial proteins are encoded by the nuclear genome and then selectively imported into one of the mitochondrial compartments. Thus, the mitochondrial OM, IM, IMS, and matrix have highly unique protein compositions. Mitochondria act "powerhouse" of the cell and have several other important functions. The numerous functions of mitochondria make them indispensable to the cell, so when a virus "hijacks" mitochondrial function, it allows it to control the whole cell. Mitochondria have important roles in several signal transduction pathways [18, 19], the process of aging [20], regulation of different biochemical pathways related to cell metabolism [21, 22], PCD [23, 24], development [25, 26], the pathogenesis of numerous diseases immune responses [19], and cell cycle control [19, 27]. The circular mitochondrial genome encodes 13 polypeptides, 2 rRNAs, and 22 tRNAs. All of these mtDNA products are essential for function of the ETC and the generation of ATP by oxidative phosphorylation [9, 27], although many proteins from the nuclear genome are also required. Thus, any injury to mtDNA can affect the whole cell. The mtDNA is more susceptible to damage from ROS because it lacks protective histones, the mitochondrion has more limited DNA repair enzymes, and it is close to ETC, the main center of ATP and ROS production. The matrix of IMS, which contains cytochrome c oxidase (Cyt C, encoded by mtDNA), SMAC/DIABLO (encoded by nuclear DNA), and endonuclease G (encoded by nuclear DNA), acts as a buffer zone between the IM and OM. This matrix region contains many of the enzymes needed for aerobic respiration, dissolved oxygen, water, carbon dioxide, and recyclable intermediates that serve as energy shuttles and have other functions.

A loss of the MMP (Δψm) leads to imbalances in the membrane potentials of the IM and OM, and then to arrest of normal cellular biosynthetic function and bioenergetics, and finally to a "crisis" within the cell. A loss of the MMP (Δψm) also leads to release of several proapoptotic Mitochondria undergo a number of processes, such as fusion and fission, in normally functioning healthy cells. However, when mitochondria develop abnormalities, the cell can destroy it by the process of mitophagy [32]. Cells typically eliminate unhealthy mitochondria by mitochondrial fission; they typically use mitochondrial fusion to recycle matrix metabolites, including mtDNA and mitochondrial membranes, for the assembly of new and healthy mitochondria. Therefore, these three processes—mitophagy, fission, and fusion—are interlinked, and they all play prominent roles in maintaining healthy cells [33]. Mitophagy plays an important role in maintaining mitochondrial homeostasis, but can also eliminate healthy mitochondria in cases such as cell starvation, viral invasion, and erythroid cell differentiation [34, 35]. The mitochondrial fusion and fission are highly dynamic. Viruses interfere with these processes to distort mitochondrial dynamic to facilitate their proliferation. Thus, interfering with these processes promotes the interference of different cellular signaling pathways [36–38]. New castal virus (NDV) uses strategy that interferes with P62-mediated mitophagy to promote viral propagation [39]. The severe acute respiratory syndrome coronovirus (SARS-CoV) escapes the innate immune response by translocating its ORF-9b to mitochondria and promotes proteosomal degradation of dynamin-like protein (Drp1) leading to mitochondrial fission [40]. However, still more studies are needed to explain the exact role of mitophagy in the viral disease pathogenesis, which regulates the cell death process [41].

increase mitochondrial fission, the recruitment of Drp by mitochondria and activation of GTPase leads to mitochondrial fission. Therefore, the EBV-induced changes in mitochondrial function, due to the LMP2A protein, may play a major role in the pathogenesis of several cancers [47].

Modulation of Mitochondria During Viral Infections http://dx.doi.org/10.5772/intechopen.73036

Infections by the herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) lead to imbalances in the calcium homeostasis of host cells. A study on rodents indicated that this calcium imbalance leads to disruption of mitochondrial function in the cervical ganglion neurons [48]. An imbalance in the cellular calcium pool affects the Miro protein (a calciumbinding protein), altering its interaction with kinesin-1. Therefore, HSV-1 and PRV "hijack" host cell proteins, and this disrupts mitochondrial dynamics, thereby allowing the viruses to

Reactive oxygen species have important roles in the overall function of normal cells and play a vital role in the host adaptive immune response [49, 50]. For example, production of O2

an important defense against microbial infections. However, a large increase in the produc-

Further studies that OS increased lung injuries caused by the influenza virus and viral replication, irrespective of the viral strain [52, 53]. Excessive and nonspecific knockdown of stressrelated enzymes, such as superoxide dismutase 2 (SOD2), led to T-cell apoptosis and many developmental defects, resulting in overall weakening of the adaptive immune system and an

Influenza A viruses encode the proapoptotic protein PB1-F2, which localizes to the mitochondria due to a target sequence on its C terminal domain. PB1-F2 is conserved within the influenza family [56]. After PB1-F2 binds to mitochondria, it interacts with two important mitochondrial proteins, VDAC1 on the OM and ANT3 on the IM [57, 58]. This leads to alterations in mitochondria morphology, release of proapoptotic proteins, loss of MMP, and then cell death.

HCV infection typically leads to generation of ROS, which interferes with the calcium signaling pathways of the cell [9]. This disruption of calcium homeostasis alters the structure of the endoplasmic reticulum, and increased calcium is taken up by the mitochondria, leading to disruption of the MMP. Recent molecular studies have shown that many other HCV proteins, such as E2 [59], and NS4B [60], are important in generating oxidative stress. In addition, the nonstructural HCV protein NS5A is an integral membrane protein that is important for viral

.−during influenza A virus infection leads to damage of lung parenchyma cells [51].

.− is

449

**3.2. Herpes simplex virus (alphaherpesvirus)**

replicate and spread to neighboring cells.

*3.3.1. Influenza A virus induces oxidative stress in mitochondria*

increased susceptibility to influenza A virus subtype H1N1 [54, 55].

*3.3.2. Influenza A virus-encoded protein PB1-F2 targets mitochondria*

*3.4.1. HCV induces oxidative stress that damages mitochondria*

**3.3. Influenza A virus**

tion of O2

**3.4. HCV virus**
