**1. Introduction**

#### **1.1. Viruses and hosts**

Viral diseases are becoming increasingly common worldwide, so it is important to identify the causative species and examine the underlying pathogenesis to prevent future epidemics and reduce the spread of new diseases. Although many host responses can contribute to the pathogenesis of viral diseases, little is known about the role of mitochondria in viral pathogenesis.

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© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

Mitochondria are suitable targets for infectious microorganisms, such as viruses, because they act as powerhouses of the cell and have various other important functions. Therefore, "hijacking" the mitochondria disrupts overall cell function and makes it easy for a virus to control the cell and propagate. The host, in turn, has several responses that it uses to protect itself from viral invasions. One defense mechanism is based on the immune system, and another is based on cell autonomy, in which cells undergo certain physiological changes upon the onset of infection, such as unscheduled activation of the cell cycle following induction by certain viral proteins. When an infected cell undergoes programmed cell death (PCD), which includes apoptosis, autophagy, and necroptosis, this can prevent the spread of the virus infection to neighboring cells. A further complication is that viruses often promote apoptosis, but they can also block apoptosis by interacting with different signaling molecules of the host cell. Many viruses, especially human viruses, can perform either function, depending on the underlying conditions. Recent studies have shown that most viruses force cells to undergo apoptosis. However, from the perspective of the virus, apoptosis of the host seems to provide no benefit, so this is a topic of the current research. Therefore, additional studies that elucidate the mechanisms underlying the induction of the virus-induced PCD and cell lysis may help to identify new drug targets for the treatment of viral infections.

#### **1.2. Intrinsic and extrinsic pathways of apoptosis in viral infections**

Programmed cell death has a key role in the pathogenesis of many conditions including viral diseases, cancer, inflammation, and neurodegenerative diseases. Apoptosis is a highly complex process that is controlled by numerous cell signaling pathways [1]. The common event at the end point is activation of a set of cysteine-aspartic proteases (caspases) [2, 3]. Apoptosis may benefit host cells by limiting the production and dissemination of viruses [4]. However, apoptosis may benefit viruses if it allows them to increase production and dissemination of progeny [5, 6]. The PCD induced by a virus infection is often described as "typical apoptosis" [7]. However, recent studies reported that nonapoptotic forms of PCD are important for the pathogenesis of certain RNA viruses, including the JC virus, hepatitis C virus (HCV), coxsackievirus B3, enterovirus, and dengue virus [8]. The mechanism of DNA virus-induced nonapoptotic cell death is not well understood. Although not all signaling pathways that induce apoptosis are fully understood, the fate of a cell undergoing apoptosis mainly depends on the balance between the Bcl-2 family sensor proteins, which can promote and inhibit apoptosis (**Figure 1**) [9–11]. Recent studies have shown viral pathogenesis that involves oxidative damage and apoptosis.

#### **1.3. Role of ROS in viral diseases**

Recent studies have shown that mitochondria are the targets of the reactive oxygen species (ROS) that are produced inside a cell during viral infections, and that mtDNA is a major target of these ROS [11]. Mitochondrial ATP generation requires proteins from the nuclear and mitochondrial genomes. ROS disrupt the oxidative production of ATP, which is required for normal cellular function, because damage of mtDNA disrupts the normal synthesis of proteins needed for mitochondria function and making them suitable targets for attack by ROS produced during infections by viruses and other microorganisms, although ROS also have other cellular targets. In HIV and hepatitis C virus infections, oxidative stress (OS) always plays a dominant pathogenic role. Peterhen and other researchers showed that almost all viruses (DNA/RNA viruses) cause cell death by generating oxidative stress in infected cells [12–14]. The OS generated during chronic hepatitis is associated with hepatic damage, a decrease in reduced glutathione (GSH) and decrease in plasma and hepatic zinc concentration [15, 16]. In case of influenza virus infection, the activated phagocytes release not only produces ROS but also cytokine and TNF. The pro-antioxidant effect of TNF may be relevant to influenza virus as shown by children with Rey's syndrome [17]. OS ultimately results in decrease in the

**Figure 1.** Modulation of cell death pathways in mitochondria by different viral infections or different viral proteins. In the extrinsic apoptosis pathway (middle left) [2], is activation of Fas death receptors at the cell surface by its ligand for activating the caspase-8 for either cleaved Bid to tBid for targeting into mitochondria [24] or activates the ROS/RIP3 mediated necroptosis via a nonmitochondria-mediated cell death process [2, 85]. In the intrinsic apoptosis pathway (top left), some death factors trigger death signals on disrupting mitochondrial function via loss of MMP and release the cytochrome c and activate the downstream caspase-3 for further triggering apoptotic cell death, but these mitochondriamediated death signaling also regulated by anti-apoptotic family members such as Bcl-2 and Bcl-xL for rescuing host cells [8, 10, 11, 87]. On the other hand, IAP can inhibit the caspase-3 activation [88] but it is suppressed by the Smac/ DIABLO molecule, which is released from mitochondria [24]. Finally, if viruses entering or expressing, they can also trigger proapoptotic signaling (indicated by black lines) or block anti-apoptotic signaling (indicated by red lines) via whole virus or viral gene productions in mammalian viruses, which is associated with activation of caspase-dependent [9] and caspase-independent executioner mechanisms [2], leads to cell death by viral genes from RNA and DNA viruses,

Modulation of Mitochondria During Viral Infections http://dx.doi.org/10.5772/intechopen.73036 445

functioning of the immune system.

respectively for inducing some damaged or human diseases [4, 27].

Mitochondria are suitable targets for infectious microorganisms, such as viruses, because they act as powerhouses of the cell and have various other important functions. Therefore, "hijacking" the mitochondria disrupts overall cell function and makes it easy for a virus to control the cell and propagate. The host, in turn, has several responses that it uses to protect itself from viral invasions. One defense mechanism is based on the immune system, and another is based on cell autonomy, in which cells undergo certain physiological changes upon the onset of infection, such as unscheduled activation of the cell cycle following induction by certain viral proteins. When an infected cell undergoes programmed cell death (PCD), which includes apoptosis, autophagy, and necroptosis, this can prevent the spread of the virus infection to neighboring cells. A further complication is that viruses often promote apoptosis, but they can also block apoptosis by interacting with different signaling molecules of the host cell. Many viruses, especially human viruses, can perform either function, depending on the underlying conditions. Recent studies have shown that most viruses force cells to undergo apoptosis. However, from the perspective of the virus, apoptosis of the host seems to provide no benefit, so this is a topic of the current research. Therefore, additional studies that elucidate the mechanisms underlying the induction of the virus-induced PCD and cell lysis may help to identify

Programmed cell death has a key role in the pathogenesis of many conditions including viral diseases, cancer, inflammation, and neurodegenerative diseases. Apoptosis is a highly complex process that is controlled by numerous cell signaling pathways [1]. The common event at the end point is activation of a set of cysteine-aspartic proteases (caspases) [2, 3]. Apoptosis may benefit host cells by limiting the production and dissemination of viruses [4]. However, apoptosis may benefit viruses if it allows them to increase production and dissemination of progeny [5, 6]. The PCD induced by a virus infection is often described as "typical apoptosis" [7]. However, recent studies reported that nonapoptotic forms of PCD are important for the pathogenesis of certain RNA viruses, including the JC virus, hepatitis C virus (HCV), coxsackievirus B3, enterovirus, and dengue virus [8]. The mechanism of DNA virus-induced nonapoptotic cell death is not well understood. Although not all signaling pathways that induce apoptosis are fully understood, the fate of a cell undergoing apoptosis mainly depends on the balance between the Bcl-2 family sensor proteins, which can promote and inhibit apoptosis (**Figure 1**) [9–11]. Recent

studies have shown viral pathogenesis that involves oxidative damage and apoptosis.

Recent studies have shown that mitochondria are the targets of the reactive oxygen species (ROS) that are produced inside a cell during viral infections, and that mtDNA is a major target of these ROS [11]. Mitochondrial ATP generation requires proteins from the nuclear and mitochondrial genomes. ROS disrupt the oxidative production of ATP, which is required for normal cellular function, because damage of mtDNA disrupts the normal synthesis of proteins needed for mitochondria function and making them suitable targets for attack by ROS produced during infections by viruses and other microorganisms, although ROS also have other

new drug targets for the treatment of viral infections.

444 Mitochondrial Diseases

**1.3. Role of ROS in viral diseases**

**1.2. Intrinsic and extrinsic pathways of apoptosis in viral infections**

**Figure 1.** Modulation of cell death pathways in mitochondria by different viral infections or different viral proteins. In the extrinsic apoptosis pathway (middle left) [2], is activation of Fas death receptors at the cell surface by its ligand for activating the caspase-8 for either cleaved Bid to tBid for targeting into mitochondria [24] or activates the ROS/RIP3 mediated necroptosis via a nonmitochondria-mediated cell death process [2, 85]. In the intrinsic apoptosis pathway (top left), some death factors trigger death signals on disrupting mitochondrial function via loss of MMP and release the cytochrome c and activate the downstream caspase-3 for further triggering apoptotic cell death, but these mitochondriamediated death signaling also regulated by anti-apoptotic family members such as Bcl-2 and Bcl-xL for rescuing host cells [8, 10, 11, 87]. On the other hand, IAP can inhibit the caspase-3 activation [88] but it is suppressed by the Smac/ DIABLO molecule, which is released from mitochondria [24]. Finally, if viruses entering or expressing, they can also trigger proapoptotic signaling (indicated by black lines) or block anti-apoptotic signaling (indicated by red lines) via whole virus or viral gene productions in mammalian viruses, which is associated with activation of caspase-dependent [9] and caspase-independent executioner mechanisms [2], leads to cell death by viral genes from RNA and DNA viruses, respectively for inducing some damaged or human diseases [4, 27].

cellular targets. In HIV and hepatitis C virus infections, oxidative stress (OS) always plays a dominant pathogenic role. Peterhen and other researchers showed that almost all viruses (DNA/RNA viruses) cause cell death by generating oxidative stress in infected cells [12–14]. The OS generated during chronic hepatitis is associated with hepatic damage, a decrease in reduced glutathione (GSH) and decrease in plasma and hepatic zinc concentration [15, 16]. In case of influenza virus infection, the activated phagocytes release not only produces ROS but also cytokine and TNF. The pro-antioxidant effect of TNF may be relevant to influenza virus as shown by children with Rey's syndrome [17]. OS ultimately results in decrease in the functioning of the immune system.
