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  • A study of patients infected with

    2019-07-30

    A study of 1833 patients infected with HIV-1 revealed that mtDNA haplogroup J and U5a posed the most significant risk for AIDS. On the other hand, mtDNA haplogroup Uk, H3 and IWX were identified as being protective against infection of AIDS [75]. As for mitochondrial participation in HIV-1 carcinogenesis, it has been shown that stimulating generation of ROS activates NF-kappa B which further upregulates the HIV-1 related gene expression through HIV-1-LTRs. As a result, various oncogenic changes accumulate which in turn triggers proliferation of infected Suramin hexasodium salt [76]. On the other hand, the high level of ROS in the mitochondrial matrix significantly raises the mutation rate of mtDNA. Over-production of ROS has also been implicated in the activation of mitochondrial glutaminase, and induction of the glutamate-mediated apoptosis pathway in the neuronal system [77].
    EBV Epstein-Barr virus (EBV) is a double helix DNA virus with a diameter of 122–180nm which was first identified in Burkitt's lymphoma cells [78]. EBV belongs to the human herpes virus type 4 (HHV-4), and B lymphocytes and epithelial cells are the main targets for its infection [79]. There are many EBV associated diseases, such as infectious mononucleosis, lymphoma, Burkitt's lymphoma and nasopharyngeal carcinoma (NPC) [80]. Among these, the most common malignant otolaryngic tumor is NPC, which has the highest mortality rate. The first indication of the implication of EBV in NPC was detection of its significantly high antibody titer in NPC patients [81]. Later, EBV DNA was also found in NPC patients [82]. Now clinically, EBV DNA is widely used to monitor the progression and recurrence of NPC [83], [84], and it is also recognized as a screening tool in research as well as a risk stratification marker in development of therapies [85]. EBV has a double-stranded, circular 172kb genome which encodes more than 90 proteins [79]. Among these, the latent membrane protein 1 (LMP1) plays an indispensable role in oncogenesis. LMP1 has been associated with a variety of important cancer-related pathways, involving NF-kB [86], [87], [88], AP-1 [88], STAT [86] and JNK [89]. Latent membrane protein 2A (LMP2A) induces a number of pathways that promote malignant cell growth through promoting metastasis and inhibiting differentiation [90]. Zta (BZLF1 or EB1) is an immediate-early protein which is expressed at the early stage of EBV infection. It is a DNA binding protein belonging to the basic leucine zipper transcription factor family [91]. It has been shown that Zta regulates the expression of transforming growth factor and fatty acid synthase genes [92], [93] and is essential for cell cycle progression [94]. mtDNA replication is initiated by transcription-mediated priming facilitated by mitochondrial single-stranded DNA binding protein (mtSSB). mtSSB is a tetramer composed of four 16kDa subunits and binds to mitochondrial DNA at the transcription and replication initiation area [95]. Zta targets mtSSB and mediates the translocation of mtSSB from mitochondria into the nuclear compartment. It thus inhibits mtDNA replication, and decreases mtDNA copy number [96]. The mitochondrial genome is also considered to be one of the genetically susceptible areas in NPC [97], [98]. Patients with NPC showed a high frequency of mutation at mtDNA np16362 [99]. An epidemiologic study was carried out in south China where the NPC incidence is much higher than in the rest of the world [100]. The impact of mtDNA haplogroup on NPC incidence was investigated in 201 NPC patients with matched controls. It was reported that patients with haplogroup R9, and its sub-haplogroup F1 in particular, exhibited the most aggressive progression of NPC [101]. EBV infection enhances the production of ROS. ROS in turn regulate cytoskeleton rearrangements and induce mitophagy and autophagy, and such regulation is essential for tumorigenesis and metastasis. Peroxiredoxin-3 (PRDX3) is an antioxidant mitochondrial protein [102]. Inhibiting PRDX3 expression enhances metastasis with an increased mobility potential [103]. In addition, LMP2A-mediated Notch pathway enhances mitochondrial fission by elevating dynamin-related protein 1 (Drp1), which also promotes cellular migration [104].