Model animals for the study of oxidative stress from complex II
Model animals for the study of oxidative stress from complex II
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DOI：
10.1016/j.bbabio.2012.10.016
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发表时间：
2013-05-01
影响因子：
4.3
通讯作者：
Ishii, Naoaki
中科院分区：
文献类型：
--
作者：
Ishii, Takamasa;Miyazawa, Masaki;Ishii, Naoaki
线粒体具有能量产生的作用，同时作为能量代谢的副产物产生细胞内活性氧（ROS），尤其是超氧阴离子（O-2（中心点-））。O-2（中心点-）由氧转化而来，由于线粒体呼吸链中过多的电子泄漏而过量产生。众所周知，电子传递系统中的线粒体复合物I和III是主要的内源性ROS来源。我们之前已经证明复合物II的突变可以导致过多的ROS（特别是秀丽隐杆线虫的SDHC: G71E，果蝇的171E和小鼠的V69E）。此外，这导致秀丽隐杆线虫和果蝇的过早死亡以及小鼠胚胎成纤维细胞的肿瘤发生。在人类中，有报道称，作为线粒体复合体II亚基的SDHB、SDHC或SDHD的突变经常导致遗传性头颈部副神经节瘤（PGLs）。最近，我们利用我们独特开发的Tet-On/Off系统建立了Tet-mev-1条件转基因小鼠，该系统可以诱导突变的SDHC基因与内源性野生型SDHC基因平等和竞争性地表达。这些小鼠经历了线粒体呼吸链功能障碍，导致氧化应激。在Tet-mev-1小鼠中，线粒体氧化应激导致多个组织过度凋亡，导致新生儿发育阶段低出生体重儿和生长迟缓。Tet-mev-1小鼠在正常发育生长期后还表现出年龄依赖性的角膜生理变化，角膜上皮化延迟，角膜内皮细胞减少，Descemet膜增厚，实质变薄，角膜病理功能障碍，如角膜炎，Fuchs角膜营养不良（FCD）和可能的圆锥角膜。在这里，我们回顾了线粒体复合物II SDHC突变的mev-1动物模型中线粒体氧化应激与现象之间的关系。这篇文章是题为“呼吸复合体II：在细胞生理和疾病中的作用”的特刊的一部分。(C) 2012 Elsevier B.V.版权所有
Mitochondria play a role of energy production and produce intracellular reactive oxygen species (ROS), especially superoxide anion (O-2(center dot-)) as a byproduct of energy metabolism at the same time. O-2(center dot-) is converted from oxygen and is overproduced by excessive electron leakage from the mitochondrial respiratory chain. It is well known that mitochondrial complexes I and III in the electron transport system are the major endogenous ROS sources. We have previously demonstrated that mutations in complex II can result in excessive ROS (specifically in SDHC: G71E in Caenorhabditis elegans, 171E in Drosophila and V69E in mouse). Moreover, this results in premature death in C. elegans and Drosophila as well as tumorigenesis in mouse embryonic fibroblast cells. In humans, it has been reported that mutations in SDHB, SDHC or SDHD, which are the subunits of mitochondrial complex II, often result in inherited head and neck paragangliomas (PGLs). Recently, we established Tet-mev-1 conditional transgenic mice using our uniquely developed Tet-On/Off system, which can induce the mutated SDHC gene to be equally and competitively expressed compared to the endogenous wild-type SDHC gene. These mice experienced mitochondrial respiratory chain dysfunction that resulted in oxidative stress. The mitochondrial oxidative stress caused excessive apoptosis in several tissues leading to low-birth-weight infants and growth retardation during neonatal developmental phase in Tet-mev-1 mice. Tet-mev-1 mice also displayed precocious age-dependent corneal physiological changes, delayed corneal epithelialization, decreased corneal endothelial cells, thickened Descemet's membrane and thinning of parenchyma with corneal pathological dysfunctions such as keratitis, Fuchs' corneal dystrophy (FCD) and probably keratoconus after the normal development and growth phase. Here, we review the relationships between mitochondrial oxidative stress and phenomena in mev-1 animal models with mitochondrial complex II SDHC mutations. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease. (C) 2012 Elsevier B.V. All rights reserved.