Functional and morphological abnormalities of mitochondria in human cells containing mitochondrial DNA with pathogenic point mutations in tRNA genes.
Functional and morphological abnormalities of mitochondria in human cells containing mitochondrial DNA with pathogenic point mutations in tRNA genes.
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含有 tRNA 基因致病性点突变的线粒体 DNA 的人类细胞中线粒体的功能和形态异常。
DOI：
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发表时间：
1994
影响因子：
4.8
通讯作者：
Ikuya NonakaSS
中科院分区：
文献类型：
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作者：
J. Hayashi;Shigeo Ohtan;Yasuo Kagawan;Daisaku TakaiS;Shigeaki Miyabayashill;Keiya Tadall;H. Fukushima;K. Inui;S. Okada;Yu;Ikuya NonakaSS
将在致命性心肌病患者中发现的在tRNA（Ile）基因的核苷酸位置4269处具有点突变的mtDNA和在Alpers病患者中发现的在tRNA（Arg）基因的10410处具有点突变的mtDNA通过胞质转移到rho zero HeLa细胞中（HeLa细胞缺乏mtDNA）为了确定这些新的tRNA基因中的mtDNA突变是否是导致线粒体呼吸功能缺陷的原因，这些疾病。分离胞质杂交体克隆（具有来自患者的mtDNA的rho zero HeLa细胞的克隆），并且比较主要含有野生型mtDNA和突变型mtDNA的胞质杂交体克隆的线粒体的呼吸功能和形态。结果表明，在核基因组中没有缺陷的4269位突变mtDNA单独积累足以产生疾病表型，而10410位突变mtDNA与发病无关，反映了人类mtDNA的罕见多态性位点之一。此外，我们发现，线粒体在活细胞中显着肿胀，只有当它们主要包含致病突变的mtDNA，这表明致病突变的tRNA基因引起的线粒体功能异常总是与它们的肿胀结构。
mtDNA with a point mutation in the tRNA(Ile) gene at nucleotide position 4269 found in a patient with fatal cardiomyopathy and mtDNA with a point mutation in the tRNA(Arg) gene at 10410 found in a patient with Alpers disease were transferred cytoplasmically to rho zero HeLa cells (HeLa cells lacking mtDNA) to determine whether these novel mtDNA mutations in the tRNA genes are responsible for the defects in mitochondrial respiration function observed in these diseases. Cybrid clones (clones of rho zero HeLa cells with mtDNA from the patients) were isolated, and respiratory function and morphology of the mitochondria of the cybrid clones containing wild-type mtDNA and mutant mtDNA predominantly were compared. The results showed that accumulation of mutant mtDNA at 4269 alone without defects in the nuclear genome was sufficient to produce a disease phenotype, while mutant mtDNA at 10410 was not related to pathogenesis and reflected one of the rare polymorphic sites of human mtDNA. Moreover, we found that mitochondria in living cells were significantly swollen only when they contained predominantly the pathogenic mutant mtDNA, suggesting that the functional abnormality of mitochondria induced by pathogenic mtDNA mutations in tRNA genes is always associated with their swollen structure.