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Asymmetrical effects of deafness-associated mitochondrial DNA 7516delA mutation on the processing of RNAs in the H-strand and L-strand polycistronic transcripts
- Source :
- Nucleic Acids Research
- Publication Year :
- 2020
- Publisher :
- Oxford University Press (OUP), 2020.
-
Abstract
- In this report, we investigated the molecular mechanism underlying a deafness-associated m.7516delA mutation affecting the 5′ end processing sites of mitochondrial tRNAAsp and tRNASer(UCN). An in vitro processing experiment demonstrated that m.7516delA mutation caused the aberrant 5′ 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.
- Subjects :
- Mitochondrial DNA
AcademicSubjects/SCI00010
RNase P
Mitochondrial translation
Cell Respiration
Mutant
Apoptosis
Deafness
Biology
Mitochondrion
DNA, Mitochondrial
Cell Line
Mitochondrial Proteins
RNA and RNA-protein complexes
Genetics
Humans
RNA, Messenger
RNA Processing, Post-Transcriptional
Mitochondrial tRNA processing
RNA, Transfer, Ser
Membrane Potential, Mitochondrial
RNA, Transfer, Asp
RNA
Cell biology
Mutation
Transfer RNA
Reactive Oxygen Species
Subjects
Details
- ISSN :
- 13624962 and 03051048
- Volume :
- 48
- Database :
- OpenAIRE
- Journal :
- Nucleic Acids Research
- Accession number :
- edsair.doi.dedup.....ec46ad3451d1d2aeebd17a1cb4412199