title: Mitochondrial DNA D-loop AG/TC transition mutation in cortical neurons of mice after long-term exposure to nucleoside analogues.
abstract: 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.
authors.affiliation: Department of Hepatology and Endocrinology, Beijing You An Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Fourth General Surgery Division, Shandong Cancer Hospital, School of Medicine and Life Sciences, University of Jinan - Shandong Academy of Medical Sciences, Jinan, 250022, China.
authors.forename: Bishi
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Department of Hepatology and Endocrinology, Beijing You An Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Luxin
authors.initials: L
authors.lastname: Qiao
authors.affiliation: Department of Hepatology and Endocrinology, Beijing You An Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Hepatology and Endocrinology, Beijing You An Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Hepatology and Endocrinology, Beijing You An Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Sufang
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Infectious Diseases, Jiangsu Geriatric Hospital, Jiangsu Geriatric Medicine Research Institute, Nanjing, Jiangsu Province, 210024, China. chenjun_7006@126.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: The Fourth General Surgery Division, Shandong Cancer Hospital, School of Medicine and Life Sciences, University of Jinan - Shandong Academy of Medical Sciences, Jinan, 250022, China. hliangbb@163.com.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Section of Physiology and Biochemistry of Sports, Capital University of Physical Education and Sports, Beijing, 100191, China. wujiancupes@126.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Hepatology and Endocrinology, Beijing You An Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, 100069, China. dexi0963@yahoo.com.
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics*; D016049:Didanosine / Q000009:adverse effects; D019259:Lamivudine / Q000009:adverse effects; D061346:Laser Capture Microdissection; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009474:Neurons / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D018119:Stavudine / Q000009:adverse effects; D015215:Zidovudine / Q000009:adverse effects
chemical_list: D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D018119:Stavudine; D016049:Didanosine
keywords: D-loop region; Laser capture microdissection; Mitochondrial toxicity; Neuronal toxicity; Nucleoside analogue