Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA
Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA
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DOI：
10.1038/90976
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发表时间：
2001-08-01
期刊：
影响因子：
82.9
通讯作者：
Hayashi, JI
中科院分区：
文献类型：
--
作者：
Nakada, K;Inoue, K;Hayashi, JI
本研究通过产生携带4696碱基对缺失的mtDNA突变体（Delta mtDNA4696）小鼠，并利用细胞色素c氧化酶（COX）电子显微镜在单个线粒体水平上鉴定COX活性，研究了线粒体DNA缺失突变体（mt）的发病机制。携带Delta mtDNA4696的组织中所有线粒体COX活性正常，直到Delta mtDNA4696富集；这阻止了小鼠表达疾病表型。此外，我们没有在单个细胞内观察到cox阳性和阴性线粒体共存。这些结果表明，外源引入的携带Delta mtDNA4696的线粒体与携带正常mtDNA的宿主线粒体之间通过交换遗传内容发生了线粒体间互补。这种互补显示了线粒体特异性机制来避免缺失突变mtDNA的表达，并开启了引入具有全长DNA的线粒体的基因治疗的可能性。
Here we investigated the pathogenesis of deletion mutant mitochondrial (mt)DNA by generating mice with mutant mtDNA carrying a 4696-basepair deletion (Delta mtDNA4696), and by using cytochrome c oxidase (COX) electron micrographs to identify COX activity at the individual mitochondrial level. All mitochondria in tissues with Delta mtDNA4696 showed normal COX activity until Delta mtDNA4696 accumulated predominantly; this prevented mice from expressing disease phenotypes. Moreover, we did not observe coexistence of COX-positive and -negative mitochondria within single cells. These results indicate the occurrence of inter-mitochondrial complementation through exchange of genetic contents between exogenously introduced mitochondria with Delta mtDNA4696 and host mitochondria with normal mtDNA. This complementation shows a mitochondria-specific mechanism for avoiding expression of deletion-mutant mtDNA, and opens the possibility of a gene therapy in which mitochondria possessing full-length DNA are introduced.