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: 7346916
• 负责人: Orian S Shirihai
• 金额: $ 17.76万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7346916
• 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; non-diabetic; novel; nutrition; prevent; programs; protein expression; repaired; response; segregation; size; transmission process

Mitochondria play a key role as p-cell nutrient integrators. One of the manifestations of diabetes is the gradual reduction in mitochondria! 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 mitochondria! function during development of p-cell dysfunction and diabetes. This study takes advantage of our recent findings in p-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 p-cells prevents the appearance of inactive units, promotes larger webs and leads to Functional homogeneity. Fusion and fission events, together termed "mitochondria! dynamics" (MtDy), have been shown in other cell types to be essential for bioenergetic performance and Ca2+ delivery throughout the mitochondria! 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 mitochondria! network, while simultaneously monitoring mitochondria! membrane potential. Our preliminary studies demonstrate that p-cells have high mitochondria! 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 mitochondria! fusion and fission serve to communicate glucose-induced metabolic signals through the mitochondria! web. Environmental factors that induce diabetes, such as glucolipotoxicity (GLT). impair MtDv. resulting in gradual deterioration of mitochondria! 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 p-cell responses to glucose and GLT in culture and in cells from diabetic animals; (B) Determine factors that regulate MtDy in p-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 mitochondria! population within the p-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.

线粒体作为P细胞营养积分剂起着关键作用。糖尿病的表现之一是 线粒体逐渐减少！响应燃料产生信号的能力。原因 尚不清楚逐渐恶化。这项研究的目的是确定 线粒体恶化！ P细胞功能障碍和糖尿病的发育过程中的功能。这项研究 利用我们最近在P细胞糖尿病模型中的发现，证明了出现 每个单个细胞内线粒体的不活跃亚群，伴随着大幅度降低 所有线粒体通过融合和裂变相互作用的能力。我们发现融合的诱导和 P细胞中的裂变蛋白可以防止出现非活动单位，促进更大的网并导致 功能同质性。 融合和裂变事件一起称为“线粒体！动力学”（mTDY），已在其他细胞中显示 整个线粒体的生物能性能和CA2+递送至关重要的类型！网络。 此外，MTDY已被证明可以控制ROS诱导的凋亡信号的传播 线粒体网络。我们开发了使我们能够标记和跟踪单个线粒体的方法， 观察融合和裂变事件，并量化线粒体！网络，同时监视 线粒体！膜电位。我们的初步研究表明，P细胞的线粒体高！ 网络活动以频繁的融合和裂变表现出来。此外，裂变后，线粒体与 膜电位受损被不可逆转地隔离，表明mTDY是一种质量 控制机制。 我们假设线粒体！融合和裂变可用于传达葡萄糖诱导的代谢 通过线粒体信号！网络。诱导糖尿病的环境因素，例如糖脂肪毒性 （GLT）。损害MTDV。导致线粒体逐渐恶化！表现为 生成线粒体的亚群，其活性水平降低。 我们将：（a）测试改变mTDY会影响P细胞对葡萄糖和GLT的响应的预测 培养和来自糖尿病动物的细胞； （b）确定调节P细胞mtdy的因素，并确定 确定作为介体功能的营养参数和代谢途径； （c） 确定在葡萄糖刺激的胰岛素期间，MTDY在钙传递到线粒体中的作用 分泌，以及线粒体的损​​坏修复和质量控制！ P细胞内的人口 在GLT下。这项研究探讨了糖尿病的机制。它将检验一个新的假设 病理生理学并确定糖尿病，肥胖和代谢综合征的潜在新药物靶标。