Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology
Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology
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DOI：
10.1073/pnas.0511154103
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发表时间：
2006-02-21
影响因子：
11.1
通讯作者：
Yoon, Y
中科院分区：
文献类型：
--
作者：
Yu, TZ;Robotham, JL;Yoon, Y
高血糖引起的线粒体活性氧（ROS）产生增加被认为是糖尿病和肥胖相关临床并发症的主要原因[Brownlee， M. (2001) Nature 414, 813-820]。我们观察到，线粒体形态的动态变化与高糖诱导的ROS过量产生有关。暴露于高葡萄糖浓度后，线粒体经历快速断裂，同时ROS形成增加。用不可代谢的立体异构体l -葡萄糖孵育细胞后，没有观察到ROS增加或线粒体断裂。然而，抑制线粒体丙酮酸摄取阻断ROS增加并不能防止高糖条件下的线粒体断裂。重要的是，我们发现由裂变过程介导的线粒体断裂是高糖诱导的呼吸增加和ROS过量产生的必要组成部分。长时间暴露于高葡萄糖条件下，可能类似于未经治疗的糖尿病条件，引起ROS产生的周期性和长期增加，同时线粒体形态改变。抑制线粒体裂变可防止高葡萄糖暴露期间ROS产生的周期性波动。这些结果表明，高糖条件下线粒体形态的动态变化有助于ROS的过量产生，线粒体裂变/融合机制可能是一个以前未被认识的目标，以控制高血糖相关疾病中ROS的急性和慢性产生。
Increased production of mitochondrial reactive oxygen species (ROS) by hyperglycemia is recognized as a major cause of the clinical complications associated with diabetes and obesity [Brownlee, M. (2001) Nature 414, 813-820]. We observed that dynamic changes in mitochondrial morphology are associated with high glucose-induced overproduction of ROS. Mitochondria undergo rapid fragmentation with a concomitant increase in ROS formation after exposure to high glucose concentrations. Neither ROS increase nor mitochondrial fragmentation was observed after incubation of cells with the nonmetabolizable stereoisomer L-glucose. However, inhibition of mitochondrial pyruvate uptake that blocked ROS increase did not prevent mitochondrial fragmentation in high glucose conditions. Importantly, we found that mitochondrial fragmentation mediated by the fission process is a necessary component for high glucose-induced respiration increase and ROS overproduction. Extended exposure to high glucose conditions, which may mimic untreated diabetic conditions, provoked a periodic and prolonged increase in ROS production concomitant with mitochondrial morphology change. Inhibition of mitochondrial fission prevented periodic fluctuation of ROS production during high glucose exposure. These results indicate that the dynamic change of mitochondrial morphology in high glucose conditions contributes to ROS overproduction and that mitochondrial fission/ fusion machinery can be a previously unrecognized target to control acute and chronic production of ROS in hyperglycemia-associated disorders.