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An in vitro processing experiment demonstrated that m.7516delA mutation caused the aberrant 5\u2032 end processing of tRNASer(UCN) and tRNAAsp precursors, catalyzed by RNase P. Using cytoplasmic hybrids (cybrids) derived from one hearing-impaired Chinese family bearing the m.7516delA mutation and control, we demonstrated the asymmetrical effects of m.7516delA mutation on the processing of tRNAs in the heavy (H)-strand and light (L)-strand polycistronic transcripts. Specially, the m.7516delA mutation caused the decreased levels of tRNASer(UCN) and downstream five tRNAs, including tRNATyr from the L-strand transcripts and tRNAAsp from the H-strand transcripts. Strikingly, mutant cybrids exhibited the lower level of COX2 mRNA and accumulation of longer and uncleaved precursors of COX2 from the H-strand transcripts. Aberrant RNA metabolisms yielded variable reductions in the mitochondrial proteins, especially marked reductions in the levels of ND4, ND5, CO1, CO2 and CO3. The impairment of mitochondrial translation caused the proteostasis stress and respiratory deficiency, diminished ATP production and membrane potential, increased production of reactive oxygen species and promoted apoptosis. Our findings provide new insights into the pathophysiology of deafness arising from mitochondrial tRNA processing defects.<\/jats:p>","DOI":"10.1093\/nar\/gkaa860","type":"journal-article","created":{"date-parts":[[2020,9,23]],"date-time":"2020-09-23T11:47:27Z","timestamp":1600861647000},"page":"11113-11129","source":"Crossref","is-referenced-by-count":18,"title":["Asymmetrical effects of deafness-associated mitochondrial DNA 7516delA mutation on the processing of RNAs in the H-strand and L-strand polycistronic transcripts"],"prefix":"10.1093","volume":"48","author":[{"given":"Yun","family":"Xiao","sequence":"first","affiliation":[{"name":"Division of Medical Genetics and Genomics, The Children\u2019s 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, Zhejiang 310058, China"},{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics, The Children\u2019s 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, Zhejiang 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiufen","family":"He","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics, The Children\u2019s 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, Zhejiang 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics, The Children\u2019s 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, Zhejiang 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feilong","family":"Meng","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics, The Children\u2019s Hospital, Zhejiang University School of Medicine and National 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5067-6736","authenticated-orcid":false,"given":"Min-Xin","family":"Guan","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics, The Children\u2019s 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, Zhejiang 310058, China"},{"name":"Key Lab of Reproductive Genetics, Ministry of Education of PRC, Zhejiang University, Hangzhou, Zhejiang 310058, China"},{"name":"Joint Institute of Genetics and Genome Medicine 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