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

氧化损伤在细胞和生物体衰老中起作用的假说受到了广泛关注。线粒体内的电子传递系统中，氧主要通过复合物Ⅲ的电子泄漏而转化为超氧阴离子（O_2^-），是活性氧的主要内源性来源。我们已经证明，在复合物II的一个亚基，细胞色素B大亚基（SDHC）的突变，也导致增加O_2^-的生产，从而导致细胞凋亡和早熟衰老的秀丽隐杆线虫。最近，具有血管化头颈部肿瘤遗传倾向的个体（即，副神经节瘤）已被证明含有复合体II中的几个突变之一。为了进一步探索线粒体氧化应激对衰老和癌症的作用，我们建立了一个在SDHC基因中的泛醌结合区具有点突变的转基因细胞系。正如预期的那样，该突变增加了复合物II的O_2^-产生，并导致过量的细胞凋亡。此外，细胞凋亡的存活细胞的显著部分被转化，如通过注射到小鼠中后增加的肿瘤形成所证明的。氧化应激导致包括线粒体在内的细胞组分的损伤，并因此导致细胞凋亡。此外，氧化应激一定会导致DNA突变并导致癌症。提示线粒体的氧化应激在细胞凋亡和肿瘤发生中起重要作用，细胞凋亡导致细胞的早衰。另外，我们构建了mev-1转基因小鼠。这种突变导致过早衰老，具有几种表型，如肌肉力量下降和视力丧失。mev-1小鼠有望成为研究线粒体O_2^-致衰老和衰老相关疾病机制的模型动物。

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.