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In this report, we investigated the molecular mechanism underlying a deafness-associated tRNAIle 4295A&amp;gt;G mutation affecting a highly conserved adenosine at position 37, 3\u2032 adjacent to the tRNA\u2019s anticodon. Primer extension and methylation activity assays revealed that the m.4295A&amp;gt;G mutation introduced a tRNA methyltransferase 5 (TRMT5)-catalyzed m1G37 modification of tRNAIle. Molecular dynamics simulations suggested that the m.4295A&amp;gt;G mutation affected tRNAIle structure and function, supported by increased melting temperature, conformational changes and instability of mutated tRNA. An in vitro processing experiment revealed that the m.4295A&amp;gt;G mutation reduced the 5\u2032 end processing efficiency of tRNAIle precursors, catalyzed by RNase P. We demonstrated that cybrid cell lines carrying the m.4295A&amp;gt;G mutation exhibited significant alterations in aminoacylation and steady-state levels of tRNAIle. The aberrant tRNA metabolism resulted in the impairment of mitochondrial translation, respiratory deficiency, decreasing membrane potentials and ATP production, increasing production of reactive oxygen species and promoting autophagy. These demonstrated the pleiotropic effects of m.4295A&amp;gt;G mutation on tRNAIle and mitochondrial functions. Our findings highlighted the essential role of deficient posttranscriptional modifications in the structure and function of tRNA and their pathogenic consequence of deafness.<\/jats:p>","DOI":"10.1093\/nar\/gkaa1225","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T20:19:08Z","timestamp":1607026748000},"page":"1075-1093","source":"Crossref","is-referenced-by-count":38,"title":["A deafness-associated tRNA mutation caused pleiotropic effects on the m1G37 modification, processing, stability and aminoacylation of tRNAIle and mitochondrial translation"],"prefix":"10.1093","volume":"49","author":[{"given":"Feilong","family":"Meng","sequence":"first","affiliation":[{"name":"Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310058, China"},{"name":"Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, 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