Mitochondrial targeting of recombinant RNAs modulates the level of a heteroplasmic mutation in human mitochondrial DNA associated with Kearns Sayre Syndrome
Mitochondrial targeting of recombinant RNAs modulates the level of a heteroplasmic mutation in human mitochondrial DNA associated with Kearns Sayre Syndrome
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DOI：
10.1093/nar/gks965
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发表时间：
2013-01-01
影响因子：
14.9
通讯作者：
Tarassov, Ivan
中科院分区：
文献类型：
--
作者：
Comte, Caroline;Tonin, Yann;Tarassov, Ivan
线粒体突变是不可治愈的人类神经肌肉疾病的重要原因，大多数是异质性的：突变的线粒体DNA与野生型基因组同时存在于细胞中，致病阈值通常为突变mtDNA的> 70%。我们研究了是否可以通过专门设计的寡核苷酸降低异质性水平，通过体内递送RNA分子的途径靶向线粒体。我们用外源RNA作为载体，证明了与突变mtDNA互补的寡核苷酸可以特异性地降低培养的线粒体胞质杂交细胞中携带与Kearns塞尔综合征相关的大缺失的mtDNA的比例。这些发现可能有助于开发一种新的治疗mtDNA相关疾病的工具。
Mitochondrial mutations, an important cause of incurable human neuromuscular diseases, are mostly heteroplasmic: mutated mitochondrial DNA is present in cells simultaneously with wild-type genomes, the pathogenic threshold being generally > 70% of mutant mtDNA. We studied whether heteroplasmy level could be decreased by specifically designed oligoribonucleotides, targeted into mitochondria by the pathway delivering RNA molecules in vivo. Using mitochondrially imported RNAs as vectors, we demonstrated that oligoribonucleotides complementary to mutant mtDNA region can specifically reduce the proportion of mtDNA bearing a large deletion associated with the Kearns Sayre Syndrome in cultured transmitochondrial cybrid cells. These findings may be relevant to developing of a new tool for therapy of mtDNA associated diseases.