Stevnsner Tinna, Thorslund Tina, de Souza-Pinto Nadja C, Bohr Vilhelm A
Department of Molecular Biology, Danish Center for Molecular Gerontology, C.F. Mollers alle bldg 130, University of Aarhus, DK 8000 Aarhus, Denmark.
Exp Gerontol. 2002 Oct-Nov;37(10-11):1189-96. doi: 10.1016/s0531-5565(02)00142-0.
Reactive oxygen species (ROS) are formed in all living organisms as a by-product of normal metabolism (endogenous sources) and as a consequence of exposure to environmental compounds (exogenous sources). Endogenous ROS are largely formed during oxidative phosphorylation in the mitochondria and, therefore, mitochondrial DNA (mtDNA) is at particularly high risk of ROS-induced damage. Mitochondria are essential for cell viability, and oxidative damage to mtDNA has been implicated as a causative factor in a wide variety of degenerative diseases, and in cancer and aging. One of the most common oxidative DNA lesions is 7,8-dihydro-8-oxoguanine (8-oxoG), which can introduce G/C to T/A transversions after DNA replication. Oxidative DNA base lesions, including 8-oxoG, are repaired primarily by the base excision repair (BER) pathway. While we know much about how this pathway functions in processing the nuclear DNA lesions, little is yet known about BER in mitochondria. We have used a number of different approaches to explore the mechanisms of DNA damage processing in the mtDNA. We have been able to demonstrate that mammalian mitochondria efficiently remove 8-oxoG from their genome, and that the efficiency of 8-oxoG incision increases with age in rats and mice. Yet 8-oxoG accumulates in mtDNA during aging. Changes in mitochondrial function with age have been observed in several organisms and accumulation of DNA lesions in mtDNA with age may be an underlying cause for numerous age-associated diseases including cancer.
活性氧（ROS）在所有生物体内均会产生，它是正常新陈代谢的副产物（内源性来源），也是暴露于环境化合物的结果（外源性来源）。内源性ROS主要在线粒体的氧化磷酸化过程中形成，因此，线粒体DNA（mtDNA）特别容易受到ROS诱导的损伤。线粒体对细胞活力至关重要，mtDNA的氧化损伤被认为是多种退行性疾病、癌症和衰老的致病因素。最常见的氧化性DNA损伤之一是7,8-二氢-8-氧代鸟嘌呤（8-氧代鸟嘌呤），它可在DNA复制后导致G/C到T/A的颠换。氧化性DNA碱基损伤，包括8-氧代鸟嘌呤，主要通过碱基切除修复（BER）途径进行修复。虽然我们对该途径在处理核DNA损伤中的作用机制了解很多，但对线粒体中的BER却知之甚少。我们采用了多种不同方法来探索mtDNA中DNA损伤处理的机制。我们已经能够证明，哺乳动物线粒体能够有效地从其基因组中去除8-氧代鸟嘌呤，并且在大鼠和小鼠中，8-氧代鸟嘌呤切割的效率会随着年龄的增长而增加。然而，在衰老过程中，8-氧代鸟嘌呤会在mtDNA中积累。在几种生物体中均观察到线粒体功能随年龄的变化，mtDNA中DNA损伤随年龄的积累可能是包括癌症在内的许多与年龄相关疾病的潜在原因。
