Szczesny Bartosz, Hazra Tapas K, Papaconstantinou John, Mitra Sankar, Boldogh Istvan
Sealy Center for Molecular Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA.
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10670-5. doi: 10.1073/pnas.1932854100. Epub 2003 Sep 5.
The mitochondria are the major source of chronic oxidative stress, which has been implicated in the aging process. Along with other cellular changes, aged cells accumulate mutations in both their nuclear and mitochondrial genomes, and they contain increased amounts of oxidatively damaged mutagenic bases such as 7,8-dihydro-8-oxoguanine, suggesting age-dependent inhibition of its repair. Surprisingly, the level and activity of 8-oxoguanine-DNA glycosylase (OGG1), responsible for repair of 7,8-dihydro-8-oxoguanine, was found to be higher in the liver mitochondrial extract from old rodents than in that from young ones. We addressed this paradox by analyzing OGG1 in the mitochondria of young vs. old mouse livers, as well as in replicating vs. presenescent human fibroblasts. We show here that although the total OGG1 activity is higher in old mitochondria, a large fraction of the enzyme is stuck to the membrane in the precursor form, which could not be translocated to and processed in the mitochondrial matrix. A nearly identical phenomenon was observed with the mitochondrial uracil-DNA glycosylase responsible for repair of mutagenic uracil. These results indicate an age-dependent decline in the mitochondrial import of proteins needed for DNA repair and possibly for other functions.
线粒体是慢性氧化应激的主要来源，而慢性氧化应激与衰老过程有关。随着其他细胞变化，衰老细胞的核基因组和线粒体基因组都会积累突变，并且它们含有更多氧化损伤的诱变碱基，如7,8 - 二氢 - 8 - 氧代鸟嘌呤，这表明其修复受到年龄依赖性抑制。令人惊讶的是，负责修复7,8 - 二氢 - 8 - 氧代鸟嘌呤的8 - 氧代鸟嘌呤 - DNA糖基化酶（OGG1）的水平和活性，在老年啮齿动物肝脏线粒体提取物中比在年轻动物的提取物中更高。我们通过分析年轻与老年小鼠肝脏线粒体中的OGG1，以及复制期与衰老前人类成纤维细胞中的OGG1，来解决这一矛盾。我们在此表明，尽管老年线粒体中的总OGG1活性较高，但很大一部分该酶以前体形式附着在膜上，无法转运到线粒体基质中并进行加工。负责修复诱变尿嘧啶的线粒体尿嘧啶 - DNA糖基化酶也观察到了几乎相同的现象。这些结果表明，DNA修复及可能的其他功能所需蛋白质的线粒体导入存在年龄依赖性下降。
