Mitochondrial dynamics in beta cell function and dysfunction

β细胞功能和功能障碍的线粒体动力学

• 批准号: 7212876
• 负责人: Orian S Shirihai
• 金额: $ 33.95万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212876
• 关键词: ATP Synthesis Pathway; Acute; Address; Affect; Animal Model; Animals; Antioxidants; Apoptosis; Apoptotic; Appearance; Autophagocytosis; B-Lymphocytes; Behavior; Beta Cell; Bioenergetics; C57BL/6 Mouse; Calcium; Cell model; Cell physiology; Cells; Chimeric Proteins; Chronic; Communication; Coupling; Data; Deterioration; Development; Diabetes Mellitus; Diabetic Diet; Diet; Diffusion; Disease; Drug Delivery Systems; Environment; Environmental Risk Factor; Equilibrium; Event; Exposure to; Fatty acid glycerol esters; Frequencies; Functional disorder; GCG gene; Generations; Genes; Glucose; Goals; In Vitro; Individual; Internet; Ions; Label; Lipids; Maintenance; Mediator of activation protein; Membrane Potentials; Metabolic; Metabolic Pathway; Metabolic syndrome; Methods; Mitochondria; Modeling; Monitor; Mus; Nature; Nutrient; Obesity; Pathway interactions; Performance; Physiological; Play; Population; Proteins; Quality Control; Rate; Rattus; Reactive Oxygen Species; Regulation; Relative (related person); Reporting; Research Personnel; Resistance; Resources; Role; Signal Transduction; Staging; Stimulus; Testing; Titrations; Zucker Rats; cell type; diabetic; effusion; glucose metabolism; in vivo; insulin secretion; mitochondrial membrane; non-diabetic; novel; nutrition; prevent; programs; protein expression; repaired; response; segregation; size; transmission process

DESCRIPTION (provided by applicant): Mitochondria play a key role as b-cell nutrient integrators. One of the manifestations of diabetes is the gradual reduction in mitochondrial capacity to produce signals in response to fuels. The cause of this gradual deterioration is not yet understood. The goal of this study is to determine the mechanism of deterioration in mitochondrial function during development of b-cell dysfunction and diabetes. This study takes advantage of our recent findings in b-cell models of diabetes demonstrating the appearance of an inactive subpopulation of mitochondria within each individual cell accompanied by a drastic reduction in the ability of all mitochondria to interact through fusion and fission. We have found that induction of fusion and fission proteins in b-cells prevents the appearance of inactive units, promotes larger webs and leads to Functional homogeneity. Fusion and fission events, together termed "mitochondrial dynamics" (MtDy), have been shown in other cell types to be essential for bioenergetic performance and Ca2+ delivery throughout the mitochondrial web. Moreover, MtDy has been shown to control the propagation of ROS induced apoptotic signaling across the mitochondria) network. We have developed methods that allow us to label and track individual mitochondria, observe fusion and fission events, and quantify the mitochondrial network, while simultaneously monitoring mitochondrial membrane potential. Our preliminary studies demonstrate that b-cells have high mitochondrial networking activity manifested by frequent fusion and fission. Moreover, following fission, mitochondria with compromised membrane potential are irreversibly segregated, suggesting that MtDy serve as a quality control mechanism. We hypothesize that mitochondrial fusion and fission serve to communicate glucose-induced metabolic signals through the mitochondrial web. Environmental factors that induce diabetes, such as glucolipotoxicity (GLT). impair MtDv. resulting in gradual deterioration of mitochondrial function that is manifested by the generation of a subpopulation of mitochondria with reduced levels of activity. We will: (A) Test the prediction that altering MtDy will affect b-cell responses to glucose and GLT in culture and in cells from diabetic animals; (B) Determine factors that regulate MtDy in b-cells and identify nutrition parameters and metabolic pathways that function as the mediators; and (C) Determine the role of MtDy in calcium delivery to mitochondria during glucose-stimulated insulin secretion, and in damage repair and quality control of the mitochondrial population within the b-cell under GLT. This study explores the mechanism of diabetes. It will test a new hypothesis for its pathophysiology and identify potential new drug targets for diabetes, obesity and metabolic syndrome.

描述（由申请人提供）：线粒体作为 b 细胞营养整合者发挥着关键作用。糖尿病的表现之一是线粒体响应燃料产生信号的能力逐渐降低。这种逐渐恶化的原因尚不清楚。本研究的目的是确定 B 细胞功能障碍和糖尿病发展过程中线粒体功能恶化的机制。这项研究利用了我们最近在糖尿病 B 细胞模型中的发现，证明每个细胞内出现不活跃的线粒体亚群，同时所有线粒体通过融合和裂变相互作用的能力急剧下降。我们发现，b 细胞中融合和裂变蛋白的诱导可以防止非活性单元的出现，促进更大的网络并导致功能同质性。融合和裂变事件统称为“线粒体动力学”(MtDy)，在其他细胞类型中已被证明对于整个线粒体网的生物能性能和 Ca2+ 输送至关重要。此外，MtDy 已被证明可以控制 ROS 诱导的细胞凋亡信号在线粒体网络中的传播。我们开发了一些方法，使我们能够标记和跟踪单个线粒体，观察融合和裂变事件，量化线粒体网络，同时监测线粒体膜电位。我们的初步研究表明，b 细胞具有高线粒体网络活性，表现为频繁的融合和裂变。此外，裂变后，膜电位受损的线粒体被不可逆地分离，这表明 MtDy 可以作为质量控制机制。我们假设线粒体融合和裂变用于通过线粒体网传递葡萄糖诱导的代谢信号。诱发糖尿病的环境因素，例如糖脂毒性（GLT）。损害 MtDv。导致线粒体功能逐渐恶化，表现为活性水平降低的线粒体亚群的产生。我们将： (A) 验证改变 MtDy 将影响培养物和糖尿病动物细胞中 b 细胞对葡萄糖和 GLT 的反应的预测； (B) 确定调节 b 细胞中 MtDy 的因素，并确定充当介质的营养参数和代谢途径； (C) 确定 MtDy 在葡萄糖刺激的胰岛素分泌过程中钙输送到线粒体中的作用，以及在 GLT 下 b 细胞内线粒体群体的损伤修复和质量控制中的作用。本研究探讨了糖尿病的发病机制。它将测试其病理生理学的新假设，并确定糖尿病、肥胖和代谢综合征的潜在新药靶点。