title: A deafness-associated tRNAAsp mutation alters the m1G37 modification, aminoacylation and stability of tRNAAsp and mitochondrial function.
abstract: In this report, we investigated the pathogenic mechanism underlying the deafness-associated mitochondrial(mt) tRNAAsp7551A > G mutation. The m.7551A > G mutation is localized at a highly conserved nucleotide(A37), adjacent (3') to the anticodon, which is important for the fidelity of codon recognition and stabilization in functional tRNAs. It was anticipated that the m.7551A > G mutation altered the structure and function of mt-tRNAAspThe primer extension assay demonstrated that the m.7551A > G mutation created the m1G37 modification of mt-tRNAAspUsing cybrid cell lines generated by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mitochondrial DNA(mtDNA)-less (ρo) cells, we demonstrated the significant decreases in the efficiency of aminoacylation and steady-state level of mt-tRNAAspin mutant cybrids, compared with control cybrids. A failure in metabolism of mt-tRNAAspcaused the variable reductions in mtDNA-encoded polypeptides in mutant cybrids. Impaired mitochondrial translation led to the respiratory phenotype in mutant cybrids. The respiratory deficiency lowed mitochondrial adenosine triphosphate production and increased the production of oxidative reactive species in mutant cybrids. Our data demonstrated that mitochondrial dysfunctions caused by the m.7551A > G mutation are associated with deafness. Our findings may provide new insights into the pathophysiology of maternally transmitted deafness that was manifested by altered nucleotide modification of mitochondrial tRNA.
authors.affiliation: Division of Clinical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310058, China.|Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Division of Clinical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang 325600, China.
authors.forename: Binjiao
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Division of Clinical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Jin
authors.affiliation: Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang 325600, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Tang
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: Division of Clinical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China ppjiang@zju.edu.cn.|Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Division of Clinical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China gminxin88@zju.edu.cn.|Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310058, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Min-Xin
authors.identifier: 0000-0001-5067-6736
authors.initials: MX
authors.lastname: Guan
mesh_terms: D002460:Cell Line; D003638:Deafness / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D020871:RNA Stability; D012349:RNA, Transfer, Asp / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D055815:Young Adult
chemical_list: D012349:RNA, Transfer, Asp; D017382:Reactive Oxygen Species