Mitochondrial DNA D-loop AG/TC transition mutation in cortical neurons of mice after long-term exposure to nucleoside analogues

作者：Zhang, Yulin; Wang, Bishi; Liang, Qi; Qiao, Luxin; Xu, Bin; Zhang, Hongwei; Yang, Sufang; Chen, Jun^*; Guo, Hongliang; Wu, Jian; Chen, Dexi

来源：Journal of NeuroVirology, 2015, 21(5): 500-507.

DOI：10.1007/s13365-015-0347-x

• D-loop region
• Laser capture microdissection
• Mitochondrial toxicity
• Neuronal toxicity
• Nucleoside analogue

With the wide application of combined antiretroviral therapy, the prognosis of human immunodeficiency virus (HIV)-1 infected patient has been significantly improved. However, long-term administration of antiretroviral drugs can result in various drug-associated toxicities. Among them, nucleoside analogues were confirmed to inhibit DNA polymerase gamma, resulting in mitochondrial toxicity. Our previous study indicated that long-term exposure of mice to nucleoside analogue could induce mitochondria DNA (mtDNA) loss in cortical neurons. Herein, we further identify mitochondrial toxicity of four nucleoside analogues (zidovudine (AZT), stavudine (D4T), lamivudine (3TC), and didanosine (DDI)) by cloning and sequencing mtDNA D-loop region in mice neurons captured with laser capture microdissection. The results showed that mutation of neuronal mtDNA D-loop sequences increased in mice treated with each of the four nucleoside analogues for 4 months and D4T and DDI induced more severe D-loop lesion than the other two nucleoside analogues. The major type of D-loop point mutations induced by four nucleoside analogues was transition, in particular of "A -> G" and "T -> C" transition, but the point transition sites were variable. Our findings suggest that long-term exposure to nucleoside analogue can result in mtDNA D-loop region lesion in mouse cortical neurons.

• 出版日期2015-10
• 单位江苏省省级机关医院; 山东省医学科学院; 济南大学; 首都医科大学