Balkan Journal of Medical Genetics

ANALYSIS OF MITOCHONDRIAL TRANSFER RNA MUTATIONS IN BREAST CANCER
Ding H.J.1, Zhao Y.P.2, Jiang Z.C.3, Zhou D.T.4, Zhu R.1* Han-Jie Ding and Ya-Ping Zhao contribute equally for this work
*Corresponding Author: Ph.D. Rui Zhu, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Binwen Road No. 548, Hangzhou, P.R. China. Phone/Fax: 0086-0571-86633133, E-mail: zhuruizjtcm@yeah.net
page: 15

DISCUSSION

In this study, the frequencies of mt-tRNA mutations in tissue samples of 80 breast cancer patients and matched normal tissues were analyzed by direct sequencing. As a result, we identified five possibly pathogenic mutations: tRNAVal G1606A, tRNAIle A4300G, tRNASer(UCN) T7505C, tRNAGlu A14693G and tRNAThr G15927A that may be associated with breast cancer. G1606A affected the acceptor arm of tRNAVal, which was extremely conserved from different species and was anticipated to disrupt the G5-C68 base-pairing. This mutation was first described in patients with neurological diseases [27]. Single fiber studies suggest that, in COX-negative fibers, a markedly increased amount of mutant mtDNA was observed, indicating that the G1606A may lead to mitochondrial dysfunction [28]. Moreover, the heteroplasmic A4300G mutation occurred at very conserved region in tRNAIle. Molecular and biochemical analysis suggested that the A4300G mutation influenced the steady-state level of tRNAIle and decreased the activities of respiratory chain complexes and has been regarded as a pathogenic mutation for cardiomyopathy [29,30]. In addition, the deafness-associated T7505C mutation was located at position 11 in the conserved base of the D-arm of tRNASer(UCN), which abolished the A11-T24 basepairing [31]. Using the cybrid cells containing the T7505C mutation, mutant cell lines caused a markedly decreased in the steady-state level of tRNASer(UCN), as compared with the controls [32]. Furthermore, the T7505C mutation resulted in reductions in Complex I, II, III and IV, and increased ROS production [32]. On the other hand, the A14693G mutation was first reported in a patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome [33]. A14693G resided at conserved base in the TΨC-loop of tRNAGlu [34]. Previous genetic studies revealed that this mutation enhanced the penetrance of deafness and Leber’s Hereditary Optic Neuropathy (LHON)-associated primary mutations in Chinese families [35, 36]. In addition, the G-to-A substitution at 15927 occurred at position 42 in the anticodon loop of tRNAThr, which abolished the very conserved Watson-Crick base-pairing (28C-42G). Functional analysis indicated that G15927A mutation led to an approximately 80% drop in tRNAThr expression level, as well as the ~39% reduction in aminoacylation ability of tRNAThr [37]. Moreover, the G15927A mutation decreased the mitochondrial membrane potential (MMP) and ATP production, and enhanced ROS production [38]. We next examined the mtDNA copy number and ATP levels in seven patients with mt-tRNA pathogenic/ likely pathogenic mutations and controls. As a result, we noticed that patients with these mutations had lower levels of mtDNA content and ATP when compared with the controls. In fact, the mtDNA copy number represented the number of mitochondria per cell and number of mitochondrial genomes per mitochondrion, being a biomarker of mitochondrial function [39]. Reductions in mtDNA copy number in cells can impair mitochondrial respiration and cause pathology including cancers [40]. Furthermore, reduction in mtDNA copy number will result an increasing in ROS production [41]. The over-production of ROS will lead to serious consequence such as increasing the oxidative stress in cells, damaging DNA; RNA; lipids and contributing to programmed cell death [42]. In addition, the respiratory chain of mitochondria was coupled with the phosphorylation of ADP in the process of electron transfer. Under the action of ATP synthase, ADP and 1‐molecule phosphate were combined to form ATP, providing energy for life activities. The activity of respiratory chain complex directly affected OXPHOS function of mitochondria and decreased the ATP production in breast cancer tissues with mt-tRNA mutations. The decreased in mtDNA copy number and ATP suggested the impairment of mitochondrial functions. Therefore, these mt-tRNA mutations caused the failures in tRNA metabolism and led to mitochondrial dysfunctions that were responsible for breast cancer. In summary, this study suggested that mutations in mt-tRNAs are involved in breast carcinogenesis. Pathogenic mt-tRNA mutations may cause mitochondrial dysfunctions and play active roles in breast cancer. Mutational analysis of mt-tRNA genes were recommended, especially for those patients who had a family history of breast cancer. Declaration of Interest. The authors report no conflicts of interest. Funding. This work was supported by the grants from Zhejiang Public Welfare Program Application Research Project (No. LGF20H280002) and Foundation of Zhejiang Chinese Medical University (No. 2021ZZ04).

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