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

INTRODUCTION

Breast carcinoma is one of the most frequent malignancy in females and poses a big threaten to women [1]. Breast carcinogenesis is a very complex progression with unknown etiology [2], knowledge of the genetic causes is still incomplete [3]. Among the genetic factors, mtDNA is involved in energy generation process. Normal cells use mitochondrial OXPHOS for energy production, whereas breast cancer cells depend on aerobic glycolysis to generate energy [4]. The altered metabolic activities can be linked to mitochondrial dysfunction that increases reactive oxygen species (ROS), promotes uncontrolled growth, and causes DNA damage in breast cancer [5]. The human mitochondrial genome is composed of 16569-bp in a double-chain structure characterized by high mutation rate and maternal inheritance [6,7]. Poorly protected mtDNA is sensitive to oxidative stress and other genotoxic damage [8]. mtDNA alternations are considered as the emerging factors which provoke breast cancer formation and progression [9,10]. For instance, mutations in the mitochondrial D-loop may alter the affinity of this region for transcripts involved in promotion of mtDNA replication, transcription, and protein production, leading to the development of breast cancer malignancy [11,12]. Furthermore, recent experimental studies revealed that mutations in OXPHOS genes, which cause impairments of respiration chain function, were involved in the metastasis of breast cancer [13,14]. Although human mt-tRNA is a relatively small molecule which accounts for only 4-10% of total RNAs, a large amount pathogenic mtDNA mutations are located in this region [15]. In fact, almost every tRNA has a wellconserved secondary structure including four stems and three loops, and plays important roles in mitochondrial translation [16]. Mutations in mt-tRNAs can affect the processes of transcription and translation, which subsequently leads to mitochondrial respiratory chain dysfunction, and are associated with a wide range of clinical diseases [17]. However, to date, no studies have been performed which assess the frequencies of mt-tRNA mutations and breast cancer. With the purpose of understanding the relationship between mt-tRNA mutations and breast cancer, a total of 80 tissues that are derived from breast cancer patients and 80 matched normal tissues were enrolled for this mutational screening. After genetic amplifications and mtDNA sequence analysis, five possible pathogenic mt-tRNA mutations were identified. To see the contributions of these mutations to mitochondrial dysfunctions, the mtDNA copy number and ATP were analyzed.

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