*3.4.1. HCV induces oxidative stress that damages mitochondria*

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 replication, apoptosis, immune responses (such as interferon resistance), and changes in cellular calcium [61]. The proteins NS5Aand NS3 have roles in increasing calcium uptake and in the oxidation of glutathione (GSH) to glutathione disulfide (GSSG) in mitochondria, which ultimately leads to oxidative stress [61–63]. The imbalance of ROS created in the mitochondria leads to activation and translocation of NF-B and STAT3 to the nucleus, as part of disease progression. Antioxidants block the NS5A-mediated activation of NF-B and STAT3 [64]. NS4B also promotes translocation of NF-B to the nucleus in a PTK-mediated pathway. The resulting production of ROS and nitric oxide (NO) causes oxidative damage and inhibits DNA repair [60] and leads to apoptosis. ROS-mediated disruption of mitochondria is believed to be the sole cause of liver inflammation in HCV infections [9].

of the host and virus at the molecular level is needed to develop new antiviral drugs and vaccines. There is an urgent need to find more effective therapeutic agents for the treatment of viral infections. Researchers have recently started testing treatments based on RNA interference (RNAi), using either microRNA (miRNA) or small interfering RNA (siRNA). Although this approach is still in its infancy, there has been some success in silencing the viral genes

Modulation of Mitochondria During Viral Infections http://dx.doi.org/10.5772/intechopen.73036 451

RNAi is an endogenous defense that cells use as a defense against harmful nucleic acids, either generated by the cell itself or from external environment (such as a viral invasions) [75]. RNAi is successful against many virus infections, but the delivery and stability of RNAi molecules within the cell are major concerns. The stability of RNAi is affected by its charge and biochemical activity within a cell, so these two parameters must be considered when designing RNAi-based therapies. In addition, the effectiveness of RNAi-based therapies depends on the delivery route [76], target gene [77, 78], target pathogen [75, 78], and target tissue [75]. The adverse effects of using RNAi-based treatment on the environment and treatment costs must also be considered, and we must have a deeper understanding of RNAi at the molecular level. The growing interest of molecular virologists in the use of RNAi suggests that this is one of

the most exciting new therapeutic approaches for treatment of viral diseases [75].

The increased generation of ROS and reactive nitrogen species (RNS) is a key part of the pathogenesis of many virus infections. OS induces loss of the MMP, so mitochondria are become more susceptible to ROS damage. However, cells also have defenses against ROS, such as reduced glutathione (GSH),which acts as an antioxidant during the oxidative production of ATP in healthy cells [9, 79–81]. An imbalance between the generation of ROS and ROS quenching by the cell's endogenous antioxidant defense system usually leads to a disease and is common during viral invasion. In recent years, due to the unavailability of antiviral drugs, researchers have proposed a number of new strategies to protect against free radical-induced OS. These strategies may be characterized as repair and protection. Protection is achieved by enzymes and by nonenzymatic compounds, such as carotenoids, vitamin C, vitamin E, GSH, and flavonoids [82]. Recent studies have shown the importance of both classes of these mol-

Identifying the main cause of a new epidemic is the most important factor in controlling disease outbreak. Many host responses appear to contribute to the pathogenesis of viral infections, and recent cellular and molecular studies have shown that many viruses specifically target mitochondria. Several different host responses and viral proteins directly or indirectly act on the mitochondria and lead to loss of the MMP. Mitochondria play important roles in cell survival and cell death, so a better understanding how different viruses use mitochondrial responses to control cells may provide a foundation for the development of new treatments for different viral diseases. More specifically, clarification of the roles of viruses

**4.2. Host antioxidant defense system fights viral invasion**

ecules in defense against oxidative stress [9, 83–86].

**5. Concluding remarks**

responsible for virulence [73, 74].

#### *3.4.2. HCV-encoded proteins target mitochondria*

HCV remains persistent in its host because it lowers the host cell immune response. The HCV protein NS3/4A is a serine protease that inhibits interferon beta production by the retinoic acid-inducible gene I (RIG-I) pathway. Studies of the NS3/4A protein show that this protease cleaves MAVS at Cys-508, a few residues before its mitochondrial targeting domain. Cleavage of MAVS inactivates this protein because its soluble form is not functional. NS3/4A has a mitochondrial localizing signal, so it can directly cleave MAVS in the mitochondria [65, 66]. Substitution of Cys-508 with arginine prevents cleavage of MAVS. Cleavage of MAVS is thus an important mechanism by which HCV reduces host cell defenses [66].
