Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction. Functional integrity of mitochondrial DNA from aged subjects.
Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction. Functional integrity of mitochondrial DNA from aged subjects.
复制标题
核基因组而非线粒体基因组参与人类年龄相关的线粒体功能障碍。
DOI：
10.1016/s0021-9258(17)37457-4
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Shigeaki Miyabayashigl
中科院分区：
文献类型：
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作者：
J. Hayashi;Shigeo Ohtall;Yasuo Kagawall;Hiroshi Kondo;Hideki KanedaSS;Hiromichi YonekawaSS;Daisaku TakaiS;Shigeaki Miyabayashigl
用皮肤成纤维细胞和无线粒体DNA的HeLa细胞(Rho o-HeLa细胞)进行细胞间转移，研究线粒体DNA和核基因组在人类衰老中的作用。我们在活体内发现，从16名不同年龄(0-97岁)的捐赠者获得的人皮肤成纤维细胞中，细胞色素c氧化酶的活性与年龄相关。老年献血员线粒体异常不是由于mtDNA分子拷贝数减少或缺失突变型mtDNA分子拷贝数增加所致，而是线粒体多肽合成显著减少所致。然而，细胞间线粒体DNA转移实验表明，来自老年捐赠者的成纤维细胞线粒体DNA功能完整。相反，将HeLa核转移到老年供者的成纤维细胞中，恢复了细胞色素c氧化酶的活性，表明与年龄相关的表型是核隐性的。然而，在随后培养这些杂交种的过程中，这种活性再次逐渐降低，并伴随着逐渐的染色体丢失。这些观察结果支持这样的观点，即核隐性体细胞突变的积累，而不是mtDNA突变的积累，是在体内观察到的人皮肤成纤维细胞中与年龄相关的线粒体功能障碍的原因。
The role of mtDNA and nuclear genome in human aging was examined by their intercellular transfer using skin fibroblasts and mtDNA-less HeLa cells (rho o-HeLa cells). We found in vivo age-related reductions in the activity of cytochrome c oxidase in human skin fibroblasts obtained from 16 donors of various ages (0-97 years). The abnormality in mitochondria of the aged donors was not attributable to either decrease in the copy number of mtDNA molecules or increase in the copy number of deletion mutant mtDNA molecules, but to significant decrease in overall polypeptide synthesis in the mitochondria. However, intercellular mtDNA transfer experiments showed that fibroblast mtDNA from elderly donors is functionally intact. By contrast, intercellular transfer of HeLa nuclei to fibroblasts from aged donors restored cytochrome c oxidase activity, suggesting that the age-related phenotype was nuclear recessive. However, during subsequent cultivation of these hybrids, the activity gradually reduced again, associated with gradual chromosome loss. These observations support the idea that accumulation of nuclear recessive somatic mutations, but not mtDNA mutations, is responsible for the in vivo age-related mitochondrial dysfunction observed in human skin fibroblasts.