Mitochondrial DNA deletions and the aging heart
Mitochondrial DNA deletions and the aging heart
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DOI：
10.1016/j.exger.2006.03.014
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发表时间：
2006-05-01
影响因子：
3.9
通讯作者：
Gosslau, A
中科院分区：
文献类型：
--
作者：
Mohamed, SA;Hanke, T;Gosslau, A
线粒体DNA （mtDNA）突变似乎与广泛的人类疾病有关，并被认为是衰老的潜在因素。然而，在人类mtDNA 4977 bp缺失的年龄依赖性增加中，仍然存在许多未解之谜。比较不同组织的mtDNA拷贝数发现，心肌的mtDNA拷贝数最高，而小脑皮层的mtDNA拷贝数最低。有趣的是，mtDNA拷贝数在衰老过程中没有变化，在心脏组织中，4977 bp的mtDNA缺失量以年龄依赖的方式增加，在40岁和40岁以上表现出显著差异（p < 0.005）。对转染端粒酶（BJ-T）的人正常细胞的体外研究表明，氧化应激（OS）是一种公认的衰老诱导4977 bp缺失和点突变的启动子，实时荧光定量PCR和DHPLC分析证实了这一点。有趣的是，OS仅在转化的人成纤维细胞中通过激活内在（线粒体介导的）信号通路诱导细胞凋亡，这可以通过线粒体形态学损伤、DNA阶梯和Bax/Bcl-2比值的增加来证明。总之，在心脏组织中，4977 bp的缺失量以年龄依赖的方式增加，并且在生命的第四个十年之后更容易检测到，尽管数据中存在一些分散。由于凋亡仅在转化细胞中由线粒体介导的途径诱导，因此凋亡在老化心脏正常组织中的作用尚不清楚。(c) 2006爱思唯尔公司版权所有。
Mitochondrial DNA (mtDNA) mutations appear to be associated with a wide spectrum of human disorders and proposed to be a potential contributor of aging. However, in an age-dependent increase of the common 4977 bp deletion of human mtDNA still many unanswered questions remain. Comparing mtDNA copy levels in different tissues revealed that cardiac muscle had the highest, while the cortex cerebelli showed the lowest copy number of mtDNA in every donor. Intriguingly, mtDNA copy number showed no changes during aging, In heart tissue, the amount of 4977 bp mtDNA deletion increased in an age-dependent manner showing significant differences at the age of 40 years and older (p < 0.005). In vitro studies analyzing human normal cells transfected with telomerase (BJ-T) revealed that oxidative stress (OS)-a well accepted promoter of aging-induced 4977 bp deletion and point mutations as demonstrated by real-time PCR and DHPLC analysis. Interestingly, OS induced apoptosis only in transformed human fibroblasts by activation of the intrinsic (mitochondrial-mediated) signalling pathway as indicated by morphological damage of mitochondria, DNA laddering and increase of the Bax/Bcl-2 ratio. In conclusion, in heart tissue, the amount of the 4977 bp deletion increased in an age-dependent manner and it was more detectable after the 4th decade of life, although there was some scatter in the data. Since, apoptosis was induced by the mitochondria-mediated pathway only in transformed cells, the role for apoptosis in normal tissue of the aging heart remains unclear. (c) 2006 Elsevier Inc. All rights reserved.