Mitochondrial Dynamics in Hyperglycemic ROS Production

高血糖 ROS 产生中的线粒体动力学

• 批准号: 8018041
• 负责人: YISANG YOON
• 金额: $ 19.48万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018041
• 关键词: Animal Model; Animals; Apoptosis; Biochemical; Biological; Cell Death; Cell physiology; Cells; Diabetes Mellitus; Disease; Electron Transport; Event; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Generations; Glucose; Health; Hour; Hyperglycemia; In Vitro; MAPK3 gene; Mediating; Membrane; Methods; Mitochondria; Molecular; Morphology; Obesity; Organ; Organism; Phosphatidylinositols; Phosphotransferases; Process; Production; Reactive Oxygen Species; Recovery; Regulation; Role; Signal Pathway; Signal Transduction; Source; Structure; Testing; Transgenic Animals; cell injury; electron tomography; mitochondrial membrane; oxidative damage; prevent; therapeutic target

DESCRIPTION (provided by applicant): The hyperglycemic complications in diabetes and obesity are causally associated with overproduction of reactive oxygen species (ROS). A major source of ROS generation in hyperglycemic conditions is thought to be the mitochondrial electron transport chain. This proposal is to define the role of mitochondrial fission in regulating ROS production in hyperglycemic conditions. We have found that mitochondria undergo rapid fragmentation and recovery within an hour of exposure of cells to a high glucose concentration, which occurs concomitantly with an increase and decrease of ROS levels. In prolonged incubation in high glucose conditions, the ROS level increased again after the initial short burst and remained high for an extended period. We observed increased cell death through apoptosis after the prolonged incubation in high glucose, indicating that a continuous high level of ROS is the cause of hyperglycemic damage. Importantly, we found that blocking mitochondrial fragmentation by inhibiting mitochondrial fission prevents the high glucose-induced ROS overproduction. Although ROS-mediated damages in hyperglycemia have been studied extensively, how mitochondria overproduce ROS in hyperglycemic conditions is not well understood. Our findings indicate that mitochondrial dynamics are an important factor that regulates ROS generation in high glucose conditions. In this proposal, we will study how mitochondrial fission participates in the upstream and downstream processes of hyperglycemia-induced ROS production. Therefore, the Central Hypothesis of this proposal is that signals elicited from high glucose stimulation alter mitochondrial dynamics and structure, resulting in ROS production and cell injury. We will, first, investigate high glucose-mediated signaling pathways that regulate mitochondrial fission, second, study how altered mitochondrial morphology causes ROS overproduction in high glucose conditions, and third, test the proof-of-principle for mitochondrial fission as a potential target to reduce the hyperglycemia-induced oxidative damages. PUBLIC HEALTH RELEVANCE Information from these studies will expand the potential targets for controlling the hyperglycemia-induced damages in diabetes and obesity, and greatly increase our understanding of how mitochondrial dynamics contribute to the regulation of mitochondrial function and cell physiology in health and disease.

描述（由申请人提供）：糖尿病和肥胖症的高血糖并发症与活性氧（ROS）的过量生产有因果关系。高血糖条件下ROS产生的主要来源被认为是线粒体电子传输链。该建议是定义线粒体裂变在调节高血糖条件下ROS产生中的作用。我们发现，线粒体在细胞暴露于高葡萄糖浓度的一个小时内经历了快速的碎裂和恢复，这与ROS水平的增加和降低时同时发生。在高葡萄糖条件下的长时间孵育中，在初始短爆发后，ROS水平再次升高，并且长时间保持高。我们观察到在高葡萄糖中长时间孵育后通过凋亡增加了细胞死亡，这表明连续的高水平ROS是造成高血糖损伤的原因。重要的是，我们发现通过抑制线粒体裂变来阻断线粒体碎片，可防止高葡萄糖诱导的ROS过量产生。尽管已经对高血糖中的ROS介导的损害进行了广泛的研究，但线粒体在高血糖条件下的产生过度产生ROS尚不清楚。我们的发现表明，线粒体动力学是调节高葡萄糖条件下ROS产生的重要因素。在此提案中，我们将研究线粒体裂变如何参与高血糖诱导的ROS产生的上游和下游过程。因此，该提案的中心假设是高葡萄糖刺激引起的信号改变了线粒体动力学和结构，从而导致ROS产生和细胞损伤。首先，我们将研究调节线粒体裂变的高葡萄糖介导的信号通路，其次研究如何改变线粒体形态会导致高葡萄糖条件下的ROS过量产生，第三，第三，测试线粒体裂变的原则证明作为潜在的靶标，以减少高糖类诱导的氧化剂量的氧化剂量。 这些研究中的公共卫生相关性信息将扩大控制高血糖引起的糖尿病和肥胖症损害的潜在目标，并大大增加了我们对线粒体动力学如何有助于对线粒体功能和健康和疾病中细胞生理的调节的理解。