**5. Concluding remarks**

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

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

Hepatitis B virus x protein (HBx) is potentially essential for viral replication, and it has oncogenic properties in animal models [67]. HBx sensitizes hepatocytes to apoptosis induced by stimuli such TNF-α [68]. Studies of the overexpression of HBx showed that this protein causes apoptosis by causing a perinuclear clustering of mitochondria and a loss of the MMP [69]. Studies of HBx mutants identified that certain hydrophobic residues (a mitochondrial targeting sequence, MTS) are important for its induction of mitochondrial localization, loss of MMP, and cell death [70]. The HBx protein usually interacts with at least two mitochondrial proteins, heat shock protein 60 (HSP60) [71] and HVDAC3 [72]. The interaction of HBx with these two proteins (which are important in maintaining mitochondrial integrity) ultimately disrupts mitochondrial function in infected cells. These two mitochondrial proteins play major roles in chronic liver disease and carcinogenesis. Therefore, HBx plays a major role in

the pathogenesis of HBV infection due to its alteration of host cell mitochondria.

**4.1. RNA interference treatment of viral diseases that target mitochondria**

Despite the many advances in molecular biology and in treatment of viral diseases, the prevention and control of viral infections remains a challenge. Alteration of the interaction of the virus and host is one general strategy. Therefore, a complete understanding of the interactions

the sole cause of liver inflammation in HCV infections [9].

an important mechanism by which HCV reduces host cell defenses [66].

*3.4.2. HCV-encoded proteins target mitochondria*

450 Mitochondrial Diseases

**3.5. Hepatitis B virus targets mitochondria**

**4. Control strategies**

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 and viral proteins in host mitochondria may help to develop methods that protect against pathogenic viruses. Therefore, molecular examination of the exact roles of viruses and viral proteins on mitochondria may help to guide the discovery of novel therapeutic strategies and provide important insights into different mitochondrial viral diseases. However, there are major unanswered questions regarding the mechanism of virus- and protein-induced loss of the MMP. Answering these questions may lead to the discovery of key molecules or pathways involved in loss of MMP, a common feature in the pathogenesis of many viral diseases. The research summarized in this review clearly shows that mitochondria are the main target of invading viruses, and that disruption of mitochondrial function is a major part of the pathogenesis of viral diseases. Although the prevention and treatment of viral diseases is challenging, molecular pathogenesis studies examining virus-host interactions will help in the design of new drugs and therapeutic strategies against different viral diseases.

VDAC voltage-dependent anion channel HIV human immunodeficiency virus IAPs inhibitor of apoptosis proteins.

\*Address all correspondence to: jrhong@mail.ncku.edu.tw

Kung University, Tainan City, Taiwan, ROC

of Virology. 2005;**79**:8262-8274

Immunology. 2002;**3**:1013-1018

of Cell Biology. 2014;**2014**:467-452

and Jiann-Ruey Hong1,3\*

Modulation of Mitochondria During Viral Infections http://dx.doi.org/10.5772/intechopen.73036 453

1 Lab of Molecular Virology and Biotechnology, Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan City, Taiwan, ROC

2 Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng

3 Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University,

[1] Liu J, Chen I, Kwang J. Characterization of a previously unidentified viral protein in porcine circovirus type 2-infected cells and its role in virus-induced apoptosis. Journal

[2] Ashkenazi A, Dixit VM. Death receptors: Signaling and modulation. Science. 1998;**281**:

[4] Benedict CA, Norris PS, Ware CF. To kill or be killed: Viral evasion of apoptosis. Nature

[5] Wong J, Zhang J, Si X, Gao G, Mao I, et al. Autophagosome supports coxsackie virus B3

[6] Lee YR, Lei HY, Liu MT, Wang JR, Chen SH, et al. Autophagic machinery activated by

[7] Levine AJ. The cellular gatekeeper for growth and division. Cell. 1997;**1997**(88):323-331 [8] Rao L, White E. Bcl-2 and the ICE family of apoptotic regulators: Making a connection.

[9] Reshi L, Su YC, Hong JR. RNA viruses: ROS-mediated cell death. International Journal

[3] Münz C. Viral evasion of autophagy. Cell Host & Microbe. 2007;**1**:9-11

replication in host cells. Journal of Virology. 2008;**82**:9143-9153

Current Opinion in Genetics & Development. 1997;**7**:52-58

dengue virus enhances virus replication. Virology. 2008;**374**:240-248

**Author details**

Latif Reshi1,2, Hao-Ven Wang2

Tainan City, Taiwan, ROC

**References**

1305-1308
