Asymmetrical effects of deafness-associated mitochondrial DNA 7516delA mutation on the processing of RNAs in the H-strand and L-strand polycistronic transcripts.
Asymmetrical effects of deafness-associated mitochondrial DNA 7516delA mutation on the processing of RNAs in the H-strand and L-strand polycistronic transcripts.
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耳聋相关线粒体 DNA 7516delA 突变对 H 链和 L 链多顺反子转录本中 RNA 加工的不对称影响
DOI：
10.1093/nar/gkaa860
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发表时间：
2020-11-04
影响因子：
14.9
通讯作者：
Guan MX
中科院分区：
文献类型：
--
作者：
Xiao Y;Wang M;He Q;Xu L;Zhang Q;Meng F;Jia Z;Zhang F;Wang H;Guan MX
在这份报告中，我们研究了与遗传相关的m.7516delA突变影响线粒体tRNAAsp和tRNASer（UCN）5′端加工位点的分子机制。体外加工实验表明，m.7516delA突变导致RNase P催化的tRNASer（UCN）和tRNAAsp前体的异常5′端加工。我们证明了m.7516delA突变对重（H）链和轻（L）链多顺反子转录物中tRNA加工的不对称影响。特别地，m.7516delA突变导致tRNASer（UCN）和下游5种tRNA的水平降低，包括来自L-链转录物的tRNATyr和来自H-链转录物的tRNAAsp。引人注目的是，突变体胞质杂交体表现出较低水平的COX 2 mRNA和积累的较长的和未切割的前体COX 2的H-链转录。异常的RNA代谢导致线粒体蛋白质的可变减少，尤其是ND 4、ND 5、CO 1、CO 2和CO 3水平的显著减少。线粒体翻译功能障碍引起蛋白质稳态应激和呼吸功能障碍，ATP生成减少，膜电位降低，活性氧生成增加，促进细胞凋亡。我们的研究结果为线粒体tRNA加工缺陷引起的耳聋的病理生理学提供了新的见解。
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.
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DOI：
10.1083/jcb.201709172
发表时间：
2017-12-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kawamata H;Manfredi G
通讯作者：
Manfredi G
影响因子：
5.3
作者：
Guan, MX;Enriquez, JA;Attardi, G
通讯作者：
Attardi, G
DOI：
10.1073/pnas.1616061113
发表时间：
2016-11-15
影响因子：
11.1
作者：
Ceriani, Federico;Pozzan, Tullio;Mammano, Fabio
通讯作者：
Mammano, Fabio
影响因子：
30.8
作者：
ENRIQUEZ, JA;CHOMYN, A;ATTARDI, G
通讯作者：
ATTARDI, G
影响因子：
14.9
作者：
Chen, Danni;Zhang, Zengming;Guan, Min-Xin
通讯作者：
Guan, Min-Xin