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      A Deafness- and Diabetes-associated tRNA Mutation Causes Deficient Pseudouridinylation at Position 55 in tRNAGlu and Mitochondrial Dysfunction.

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          Abstract

          Several mitochondrial tRNA mutations have been associated with maternally inherited diabetes and deafness. However, the pathophysiology of these tRNA mutations remains poorly understood. In this report, we identified the novel homoplasmic 14692A→G mutation in the mitochondrial tRNAGlu gene among three Han Chinese families with maternally inherited diabetes and deafness. The m.14692A→G mutation affected a highly conserved uridine at position 55 of the TΨC loop of tRNAGlu The uridine is modified to pseudouridine (Ψ55), which plays an important role in the structure and function of this tRNA. Using lymphoblastoid cell lines derived from a Chinese family, we demonstrated that the m.14692A→G mutation caused loss of Ψ55 modification and increased angiogenin-mediated endonucleolytic cleavage in mutant tRNAGlu The destabilization of base-pairing (18A-Ψ55) caused by the m.14692A→G mutation perturbed the conformation and stability of tRNAGlu An approximately 65% decrease in the steady-state level of tRNAGlu was observed in mutant cells compared with control cells. A failure in tRNAGlu metabolism impaired mitochondrial translation, especially for polypeptides with a high proportion of glutamic acid codons such as ND1, ND6, and CO2 in mutant cells. An impairment of mitochondrial translation caused defective respiratory capacity, especially reducing the activities of complexes I and IV. Furthermore, marked decreases in the levels of mitochondrial ATP and membrane potential were observed in mutant cells. These mitochondrial dysfunctions caused an increasing production of reactive oxygen species in the mutant cells. Our findings may provide new insights into the pathophysiology of maternally inherited diabetes and deafness, which is primarily manifested by the deficient nucleotide modification of mitochondrial tRNAGlu.

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          Author and article information

          Journal
          J. Biol. Chem.
          The Journal of biological chemistry
          American Society for Biochemistry & Molecular Biology (ASBMB)
          1083-351X
          0021-9258
          Sep 30 2016
          : 291
          : 40
          Affiliations
          [1 ] From the Division of Clinical Genetics and Genomics, Children's Hospital and the Institute of Genetics, Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 310001.
          [2 ] the Institute of Genetics, Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 310001.
          [3 ] the Department of Otolaryngology, Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China 325035, the Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China 325035.
          [4 ] the Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China 325035.
          [5 ] the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 200031, and.
          [6 ] the Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, 67084 Strasbourg, France.
          [7 ] From the Division of Clinical Genetics and Genomics, Children's Hospital and the Institute of Genetics, Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 310001, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, and Joining Institute of Genetics and Genomic Medicine between Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, Zhejiang, China 310058, gminxin88@zju.edu.cn.
          Article
          M116.739482
          10.1074/jbc.M116.739482
          5076513
          27519417
          d10d7afe-c818-4444-af1e-f7c5c302b88a
          History

          mitochondrial disease,mtDNA,mutant,pathogenesis,posttranslational modification (PTM),tRNA,diabetes,hearing

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