Construction and analysis of an electron transport complex II disease model mouse.

很多注意力都集中在氧化损伤在细胞和组织衰老中起作用的假设上。众所周知，氧最初是通过线粒体电子传递系统中主要的络合物III泄漏的电子而转化为超氧阴离子(O_2^-)的，O_2^-是ROS的主要内源。我们已经证明，在线虫中，复合体II的一个亚单位--细胞色素b大亚基(SDHC)的突变也会导致O_2^-的产生增加，从而导致线虫的细胞凋亡和性早衰。最近，有血管化头颈部肿瘤(即副神经节瘤)遗传倾向的个体被证明含有复合体II的几个突变之一。为了进一步探讨线粒体氧化应激在衰老和癌症中的作用，我们建立了一个点突变在SDHC基因泛醌结合区的转基因细胞系。正如预期的那样，该突变增加了复合体II产生O_2^-的能力，并导致过度的细胞凋亡。此外，很大一部分从凋亡中存活的细胞发生了转化，注射到小鼠体内后肿瘤形成增加证明了这一点。氧化应激导致包括线粒体在内的细胞成分的损伤，从而导致细胞凋亡。此外，氧化应激必然会导致DNA突变并导致癌症。提示线粒体氧化应激在导致性早衰的细胞凋亡和肿瘤发生中起重要作用。此外，我们构建了MEV-1转基因小鼠。这种突变会导致过早衰老，表现为几种表型，如肌肉力量下降和视力丧失。MEV-1小鼠被认为是从线粒体中了解衰老和衰老相关疾病的机制的模型动物。

Much attention has been focused on the hypothesis that oxidative damage plays in cellular and organismal aging. It is known that oxygen is initially converted to superoxide anion (O_2^-), one of reactive oxygen species (ROS), by electron leaked from mainly complex III in the electron transport system present in mitochondria, where it is the major endogenous source of ROS. We have shown that a mutation in a subunit, cytochrome b large subunit (SDHC), of complex II, also results in increasing O_2^- production and therefore lead to apoptosis and precocious aging in C.elegans. Recently, individuals with an inherited propensity for vascularized head and neck tumors (i.e., paragangliomas) have been demonstrated to contain one of several mutations in complex II.To further explore the role of oxidative stress from mitochondria on aging and cancer, we established a transgenic cell line with a point mutation at the ubiquinone binding region in the SDHC gene. As expected, this mutation increased O_2^- production from complex II and led to excess apoptosis. Moreover, a significant fraction of the surviving cells from the apoptosis were transformed, as evidenced by increased tumor formation after injection into mice. Oxidative stress results in the damage to the cellular components including mitochondria and, therefore leads to apoptosis. Furthermore, oxidative stress must cause mutations in DNA and leads to cancer. It is suggested that oxidative stress from mitochondria play an important role of both apoptosis, which leads to precocious aging, and cancer.In addition, we constructed the mev-1 transgenic mice. This mutation leads to premature ageing with several phenotypes such as decreasing of muscular power and lost of eyesight. The mev-1 mouse is anticipated as a model animal to understanding the mechanisms of aging and age-related disease by O_2^- from mitochondria.