Ozawa T
Department of Biomedical Chemistry, Faculty of Medicine, University of Nagoya, Japan.
Biochim Biophys Acta. 1995 May 24;1271(1):177-89. doi: 10.1016/0925-4439(95)00026-z.
Mitochondrial DNA (mtDNA) that codes protein subunits essential for the maintenance of mitochondrial ATP synthesis system acquires mutations at a much higher rate than that in nuclear DNA. Recent study has revealed that somatically acquired mutations such as deletions in mtDNA are caused mainly by oxygen free-radical damage. Cumulative accumulation of these somatic mutations during the life of an individual causes bioenergetic deficit leading to cell death and normal ageing. The base-sequencing of the entire mtDNA from 48 individuals revealed that germ-line point mutations accelerate extensively the somatic oxygen free-radical damage and the deletions leading to generation of more than a hundred kinds of mtDNA minicircle. These accelerated somatic mutations are expressed as premature ageing of the patients with degenerative diseases. Comprehensive analyses of the entire mtDNA, including the total base-sequencing and the total deletion correlating with oxygen free-radical damage, has revealed a clear relationship between the genotype and its phenotype, such as the severity of clinical symptoms and the survival time of the patients. Extensive generation of mtDNA minicircles caused by the oxygen free radical implies a close relations between the redox mechanism of ageing and the programmed cell-death machinery.
编码维持线粒体ATP合成系统所必需的蛋白质亚基的线粒体DNA（mtDNA）发生突变的速率比核DNA高得多。最近的研究表明，体细胞获得的突变，如mtDNA中的缺失，主要是由氧自由基损伤引起的。个体生命过程中这些体细胞突变的累积会导致生物能量不足，进而导致细胞死亡和正常衰老。对48个人的整个mtDNA进行碱基测序发现，生殖系点突变会广泛加速体细胞氧自由基损伤以及导致产生一百多种mtDNA小环的缺失。这些加速的体细胞突变表现为退行性疾病患者的早衰。对整个mtDNA进行全面分析，包括全碱基测序和与氧自由基损伤相关的总缺失分析，揭示了基因型与其表型之间的明确关系，如临床症状的严重程度和患者的存活时间。氧自由基导致mtDNA小环的大量产生意味着衰老的氧化还原机制与程序性细胞死亡机制之间存在密切关系。
