**3.3. Influenza A 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 patho-

During the coevolution of viruses and hosts, some viruses have evolved proteins that mimic the activity of host proteins, thereby allowing the virus to complete its life cycle without inducing an immune response in the host. For example, Mimivirus, a genus with a single species in the newly created Mimiviridae, has genes for many proteins, including a viral mitochondrial carrier protein (VMC-I) [42], which mimics the host cell's mitochondrial carrier protein, allowing it to control mitochondrial transport in infected cells. Therefore, this virus takes control of the host cell's transportation of ADP, dADP, TTP, dTTP, and UTP in exchange for dATP, which the virus uses as an energy source for genome replication and production of progeny [27].

Numerous viruses appear to have adopted a "strategy" of damaging the host cell mitochondrial DNA to control the whole cell. For example, the herpes simplex virus (HSV) causes productive and latent infections in human hosts by disruption of mitochondrial function. The HSV-1UL12 gene encodes two distinct yet similar proteins, UL12 and UL12.5. UL12 is an alkaline nuclease, and UL12.5 is an N terminally truncated 500-aa polypeptide that lacks the first 126 residues of UL12. UL12 plays a crucial role in viral genome replication and processing; UL12.5 also has nuclease and strand-exchange activities but does not accumulate in the host cell nucleus. Instead, UL12.5 localizes predominantly to the mitochondria, where it triggers massive degradation of mitochondrial DNA during early HSV replication. In particular, UL12.5 occurs directly within the mitochondrial matrix, and its nuclease activity degrades mtDNA [43]. HIV and hepatitis C virus infections cause metabolic stress due to mtDNA depletion in coinfected patients [44]. The Zta protein encoded by Ebola virus (EBV) genome translocates into mitochondria and interacts with mitochondrial single-strand protein, which ultimately affects mtDNA replication [45]. The OS generated during HCV infection also interferes with mtDNA [31].

The Epstein–Barr virus (EBV) is an oncovirus that is associated with breast cancer, gastric cancer, and numerous other cancers. Recent studies showed that EBV-encoded latent membrane protein 2A (LMP2A) leads to increased mitochondrial fission [46]. Further, molecular studies showed that LMP2A activates the NOTCH pathway, which alters the expression of Drp1 and then increases mitochondrial fission. Although increased Drp expression does not directly

genesis, which regulates the cell death process [41].

448 Mitochondrial Diseases

**2.3. Role of mitochondria in host immune response**

**2.4. Viruses target mitochondrial DNA and disable host cells**

**3. Human viruses in mitochondria-mediated diseases**

**3.1. Epstein: Barr virus**

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

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 .− is an important defense against microbial infections. However, a large increase in the production of O2 .−during influenza A virus infection leads to damage of lung parenchyma cells [51]. 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 increased susceptibility to influenza A virus subtype H1N1 [54, 55].

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

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.
