Mitochondrial delivery of antisense RNA by MITO-Porter results in mitochondrial RNA knockdown, and has a functional impact on mitochondria.
Mitochondrial delivery of antisense RNA by MITO-Porter results in mitochondrial RNA knockdown, and has a functional impact on mitochondria.
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DOI：
10.1016/j.biomaterials.2015.04.022
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发表时间：
2015-07
期刊：
影响因子：
14
通讯作者：
R. Furukawa;Yuma Yamada;E. Kawamura;H. Harashima
中科院分区：
文献类型：
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作者：
R. Furukawa;Yuma Yamada;E. Kawamura;H. Harashima
线粒体基因组靶向核酸是用于治疗线粒体疾病的有前景的治疗候选物。迄今为止，已经报道了许多用于将遗传信息递送至细胞质和细胞核的系统，并且已经报道了涉及靶向细胞质和细胞核的基因递送的几种成功的基因疗法。然而，关于线粒体基因递送系统的进展要少得多，并且线粒体基因治疗从未实现。在这里，我们报告的线粒体交付的反义RNA寡核苷酸（ASO）进行线粒体RNA敲低，以调节线粒体功能。使用MITO-Porter系统的组合实现ASO的线粒体递送，所述MITO-Porter系统包含用于通过膜融合和D-臂（tRNA至基质的线粒体输入信号）进行线粒体递送的线粒体融合脂质包膜。AS0的线粒体递送诱导靶向的mRNA和蛋白质（即细胞色素氧化酶亚基II，线粒体呼吸链的组分）的敲低。此外，线粒体膜电位的去极化的呼吸链的下调作为结果的线粒体交付的ASO。这一发现构成了证明纳米载体介导的反义RNA的线粒体基因组靶向影响线粒体功能的第一份报告。
Mitochondrial genome-targeting nucleic acids are promising therapeutic candidates for treating mitochondrial diseases. To date, a number of systems for delivering genetic information to the cytosol and the nucleus have been reported, and several successful gene therapies involving gene delivery targeted to the cytosol and the nucleus have been reported. However, much less progress has been made concerning mitochondrial gene delivery systems, and mitochondrial gene therapy has never been achieved. Here, we report on the mitochondrial delivery of an antisense RNA oligonucleotide (ASO) to perform mitochondrial RNA knockdown to regulate mitochondrial function. Mitochondrial delivery of the ASO was achieved using a combination of a MITO-Porter system, which contains mitochondrial fusogenic lipid envelopes for mitochondrial delivery via membrane fusion and D-arm, a mitochondrial import signal of tRNA to the matrix. Mitochondrial delivery of the ASO induces the knockdown of the targeted mitochondria-encoded mRNA and protein, namely cytochromecoxidase subunit II, a component of the mitochondrial respiratory chain. Furthermore, the mitochondrial membrane potential was depolarized by the down regulation of the respiratory chain as the result of the mitochondrial delivery of ASO. This finding constitutes the first report to demonstrate that the nanocarrier-mediated mitochondrial genome targeting of antisense RNA effects mitochondrial function.