br Hypothesis of mtDNA instability in Warburg

Hypothesis of mtDNA instability in Warburg effect One of the most commonly adopted hypothesis to explain the association between human mtDNA instability and Warburg effect in human cancers is oxidative damage and its vicious cycle. As we know, oxidative DNA damage has been demonstrated to play an important role in the carcinogenesis of human cancers. Such an oxidative damage in human mtDNA may cause a dysregulation of human mtDNA with subsequent mitochondrial dysfunction. Impaired mitochondrial function further initiates an improper electron transport and an electron leak. The leaking electron may cause another course of oxidative mtDNA damage. Then, the vicious cycle is sustained in human cancers and the Warburg effect follows. When discussing the mtDNA instability in human cancers, most researchers paid attention to the quantitative mtDNA copy number changes and the qualitative mtDNA D-loop mutations, especially the D310 mutation, with their association to clinicopathological parameters.
Human mtDNA damage and mutation In general, nDNA is inherited from parents with equal contributions, and it is termed as heterozygotic condition. On the contrary, human mtDNA is transmitted exclusively through the maternal lineage with a single origin. Moreover, the majority of mtDNA molecules in the human order buprenorphine hydrochloride of the postmitotic tissues of an individual are assumed to be identical at birth, and such a situation is termed as “homoplasmy or homoplasmic condition.” Because of the following characteristics—absence of introns, lack of histone protection, insufficient DNA repair systems, lower fidelity of DNA polymerase gamma, and increased exposure to reactive oxygen species inside the mitochondria—human mtDNA molecules are far more susceptible to oxidative damage compared to nDNA molecules. When the mutant or damaged mtDNA variants coexist with the wild-type inborn mtDNA, the pattern of homoplasmy is disrupted and is shifted to the so-called “heteroplasmy or heteroplasmic condition.” With regard to the entire mtDNA structure, damage occurs much more easily in the D-loop region, especially in the two hypervariable regions (HV1 at np 16024–16083 and HV2 at np 57–372). Among various kinds of D-loop damage, the D310 mutation (a hot spot in HV2) is the most common one. Between np 303 and np 316 of the D-loop, there is a poly-cytidine (PCT) tract with a thymidine inserted at np 310 (5′-C303CCCCCCT310CCCCCC316-3′). As a rule, the cytidine number after thymidine remains constant as 6. However, the cytidine number prior to thymidine is highly variable. Generally, the cytidine number prior to the thymidine is seven (7-C, based on the rCRS), but 6-C, 8-C, and 9-C variants have also been reported. Variations of the cytidine number in the D-loop of mtDNA between np 303 and np 309 is termed as D310 polymorphism or D310 sequence variations.
Changes of mtDNA copy number in human cancers The alterations of mtDNA copy number have been evaluated in several human cancers. When compared to the noncancerous counterparts, a decrease in mtDNA copy numbers has been detected in lung cancer, hepatocellular carcinoma, gastric cancer, and breast cancer. In an analysis of 29 lung cancer tissues after neoadjuvant chemotherapy, a decrease of mtDNA copy number was associated with the progression of lung cancer. Furthermore, Wu et al demonstrated that the decrease of the mtDNA copy number was related to an advanced-stage gastric cancer. All the above findings indicated that the decrease of the mtDNA copy number in human cancers might cause a decrease of mitochondrial function. On the contrary, a progressive increase of the mtDNA copy number was noted in carcinogenesis, a spectrum among normal mucosa, mild dysplasia, moderate dysplasia, severe dysplasia, and invasive carcinoma of head and neck cancers in smokers. Also, when compared to the noncancerous counterpart, an increase of mtDNA copy number was found in thoracic esophageal squamous cell carcinoma (TESCC) and head and neck cancers, especially in those who smoked cigarettes. In TESCC, the increase of the mtDNA copy number from noncancerous esophageal mucosa to TESCC and then metastatic lymph nodes were compatible with the increase of 8-OHdG (8-hydroxyl-20-deoxyguanosine, a marker of oxidative damage on guanine) accumulation in mtDNA of the above tissues. Such an increase was supposed to compensate for the damaged mtDNA to maintain mitochondrial function in proper order. In an in vitro cell line study, it was demonstrated that the high mtDNA copy numbers were associated with a higher invasive activity in TESCC cell lines. Using the knockdown technique to decrease the expression of TFAM, a pivotal protein involved in mtDNA replication and transcription, the mtDNA copy number of TESCC was significantly decreased and the invasive activity was also suppressed. Regardless of the increase or decrease of mtDNA copy number, these mixed results among different human cancers suggested an alteration in mitochondrial function.