Mitochondrion plays important roles in cellular energy metabolism, free radical generation and apoptosis. Dysfunction of mitochondrion would result in an obstacle to ATP synthesis and then lead to a series of clinical symptom because of the energy deficiency. The genetic defects of mitochondrial DNA could lead to the dysfunctions and the mitochondrial DNA related disease currently received an increasing concern. However, the case-control design commonly adopted in this field is vulnerable to genetic background, population stratification and poor data quality. Phylogenetic analysis could help solve these problems, but it has not received adequate attention. So we performed the following studies by using the phylogenetic analysis. Firstly, we investigated the relationship between mtDNA C1494T mutation and aminoglycoside-induced and nonsyndromic hearing loss (AINHL). Mutation C1494T in mitochondrial 12S rRNA gene was recently reported in two large Chinese families with aminoglycoside-induced and nonsyndromic hearing loss (AINHL) and was claimed to be pathogenic. This mutation, however, was first reported in a sample from central China in our previous study that was aimed to reconstruct East Asian mtDNA phylogeny. All these three mtDNAs formed a subclade defined by mutation C1494T in mtDNA haplogroup A. It thus seems that mutation C1494T is a haplogroup A-associated mutation and this matrilineal background may contribute a high risk for the penetrance of mutation C1494T in Chinese with AINHL. To test this hypothesis, we first genotyped mutation C1494T in 553 unrelated individuals from three regional Chinese populations and performed an extensive search for published complete or near-complete mtDNA data sets (>3000 mtDNAs), we then screened the C1494T mutation in 111 mtDNAs with haplogroup A status that were identified from 1823 subjects across China. The search for published mtDNA data sets revealed no other mtDNA besides the above-mentioned three carrying mutation C1494T. None of the 553 randomly selected individuals and the 111 haplogroup A mtDNAs was found to bear this mutation. Therefore, our results suggest that C1494T is a very rare event. The mtDNA haplogroup A background in general is unlikely to play an active role in the penetrance of mutation C1494T in AINHL. Furthermore, we extended our study into tumor related mtDNA mutation. The role of mitochondrial dysfunction in tumorigenesis has been a subject of great interest. Although mitochondrial DNA mutations are found in various tumors recently, the question of whether such mutations contribute to the promotion of carcinoma remains unsolved. Here we performed a study on the mitochondrial DNA mutations in breast cancer. The complete mitochondrial genomes of the primary cancerous, matched paracancerous normal and distant normal tissues from 10 early-stage breast cancer patients were analyzed, with special attempts (i) to investigate whether the reported high frequency of mitochondrial DNA (mtDNA) somatic mutations in breast cancer could be repeated under a stringent data quality control, and (ii) to characterize the spectrum of mtDNA somatic mutations in Chinese breast cancer patients and evaluate their potential significance in early cancer diagnosis. Two heteroplasmic somatic mutations (T2275C and A8601G) were identified in our samples. The transition A8601G was present in the primary cancerous and paracancerous normal tissues from patient no.3. Transition T2275C was found in the primary cancerous tissue but not in other normal tissues from patient no. 6; this transition has been reported in the colonic crypts and is located at a highly conserved site in the 16S rRNA gene. Subsequent cloning sequencing confirmed the absence of both mutations in the distant normal tissues from the 2 patients. The overall rate of somatic mutations in our patients was much lower than those of previous studies of breast cancer. Our results gave support to the recent claim that the high frequency of mtDNA somatic mutations in cancer studies is overestimated. Based on the mtDNA mutation pattern in early stage breast cancer observed in this study, we cautioned the enthusiasms and efforts to look for somatic mutations that were of diagnostic value in cancer early detection. Finally, we recommend that the phylogenetic approach should be used in mitochondrial DNA related studies more deeply and widely.
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