Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species
Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species
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DOI：
10.1093/cvr/cvn104
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发表时间：
2008-07-15
影响因子：
10.8
通讯作者：
Yoon, Yisang
中科院分区：
文献类型：
--
作者：
Yu, Tianzheng;Sheu, Shey-Shing;Yoon, Yisang
目的糖尿病心血管并发症的主要原因之一是高血压引起的细胞损伤，线粒体分裂参与了细胞凋亡过程。我们研究了线粒体分裂在高糖诱导的心血管细胞injuries.Methods和结果中的作用，我们使用了几种类型的培养小鼠，大鼠和牛的心血管系统细胞，并评估线粒体形态，活性氧（ROS）水平，和凋亡参数在持续高葡萄糖孵育。腺病毒感染用于抑制分裂蛋白DLP1。我们发现，在持续高葡萄糖条件下培养的细胞中，线粒体很短，而且碎片化。在相同条件下，细胞ROS水平高，细胞死亡增加。我们证明，ROS水平的增加导致线粒体通透性转换（MPT），磷脂酰丝氨酸暴露，细胞色素C释放，和caspase激活在长期的高糖条件下。重要的是，通过在持续高葡萄糖条件下抑制线粒体分裂来维持管状线粒体使细胞ROS水平正常化，并防止MPT和随后的细胞死亡。这些结果表明，线粒体碎片是一个上游因素的ROS过度生产和细胞死亡，在长期的高糖conditions.Conclusion这些研究结果表明，分裂介导的断裂的线粒体小管是因果关系相关的线粒体ROS的生产和心血管细胞损伤在高血糖条件下。
Aims One of the main causes of cardiovascular complications in diabetes is the hyperglycaemia-induced cell injury, and mitochondrial fission has been implicated in the apoptotic process. We investigated the role of mitochondrial fission in high glucose-induced cardiovascular cell injury.Methods and results We used several types of cultured mouse, rat, and bovine cells from the cardiovascular system, and evaluated mitochondrial morphology, reactive oxygen species (ROS) levels, and apoptotic parameters in sustained high glucose incubation. Adenoviral infection was used for the inhibition of the fission protein DLP1. We found that mitochondria were short and fragmented in cells incubated in sustained high glucose conditions. Under the same conditions, cellular ROS levels were high and cell death was increased. We demonstrated that the increased level of ROS causes mitochondrial permeability transition (MPT), phosphatidylserine exposure, cytochrome c release, and caspase activation in prolonged high glucose conditions. Importantly, maintaining tubular mitochondria by inhibiting mitochondrial fission in sustained high glucose conditions normalized cellular ROS levels and prevented the MPT and subsequent cell death. These results demonstrate that mitochondrial fragmentation is an upstream factor for ROS overproduction and cell death in prolonged high glucose conditions.Conclusion These findings indicate that the fission-mediated fragmentation of mitochondrial tubules is causally associated with enhanced production of mitochondrial ROS and cardiovascular cell injury in hyperglycaemic conditions.