Asymmetrical effects of deafness-associated mitochondrial DNA 7516delA mutation on the processing of RNAs in the H-strand and L-strand polycistronic transcripts. Issue 19 (12th October 2020)

• Record Type: Journal Article
• Authors: Xiao, Yun; Wang, Meng; He, Qiufen; Xu, Lei; Zhang, Qinghai; Meng, Feilong; Jia, Zidong; Zhang, Fengguo; Wang, Haibo; Guan, Min-Xin
• Is Part Of: Nucleic acids research. Volume 48:Issue 19(2020)
• Page Start: 11113
• Page End: 11129
• Publication Date: 2020-10-12
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkaa860
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: In this report, we investigated the molecular mechanism underlying a deafness-associated m.7516delA mutation affecting the 5′ end processing sites of mitochondrial tRNA Asp and tRNA Ser(UCN) . An in vitro processing experiment demonstrated that m.7516delA mutation caused the aberrant 5′ end processing of tRNA Ser(UCN) and tRNA Asp 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 tRNA Ser(UCN) and downstream five tRNAs, including tRNA Tyr from the L-strand transcripts and tRNA Asp 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.