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

电子传递复合物II疾病模型小鼠的构建与分析。

基本信息

批准号：
14580801
负责人：
ISHII Naoaki
金额：
$ 1.54万
依托单位：
Tokai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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.

氧化损伤在细胞和机体衰老中起作用的假说引起了人们的广泛关注。已知氧最初是通过线粒体电子传递系统中主要络合物III的电子泄露转化为活性氧（ROS）之一的超氧阴离子（O_2^-），它是ROS的主要内源。我们已经证明，一个亚单位的突变，细胞色素b大亚单位（SDHC），复合体II，也导致增加O_2^-的产生，因此导致细胞凋亡和秀丽隐杆线虫的早衰。最近，具有血管化头颈部肿瘤（即副神经节瘤）遗传倾向的个体已被证明含有复合体II的几种突变之一。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SDHC基因泛素结合区点突变的转基因细胞系。正如预期的那样，这种突变增加了复合体II的O_2^-的产生，并导致过量的细胞凋亡。此外，注射到小鼠体内后，大量凋亡后的存活细胞被转化，证明肿瘤形成增加。氧化应激导致包括线粒体在内的细胞成分受损，从而导致细胞凋亡。此外，氧化应激一定会引起DNA突变并导致癌症。这表明线粒体的氧化应激在细胞凋亡（导致早衰）和癌症中都起着重要作用。此外，我们构建了mev-1转基因小鼠。这种突变导致早衰，表现为肌肉力量下降和视力丧失。mev-1小鼠有望作为一种模型动物，通过线粒体中的O_2^-来了解衰老和与年龄相关的疾病的机制。