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: 7645363
• 负责人: Orian S Shirihai
• 金额: $ 14.45万
• 依托单位: BOSTON MEDICAL CENTER
• 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/7645363
• 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细胞营养积分器起关键作用。糖尿病的表现之一是线粒体能力逐渐降低，以响应燃料而产生信号。尚未理解这种逐渐恶化的原因。这项研究的目的是确定B细胞功能障碍和糖尿病发育过程中线粒体功能中恶化的机制。这项研究利用了我们在糖尿病的B细胞模型中的最新发现，表明每个单个细胞内线粒体无活性亚群的出现伴随着所有线粒体通过融合和裂变相互作用的能力的急剧降低。我们发现，B细胞中融合蛋白的诱导和裂变蛋白可以防止出现非活性单元，促进更大的网并导致功能均匀性。在其他细胞类型中，融合和裂变事件一起被称为“线粒体动力学”（mTDY），对于整个线粒体Web中的生物能性能和Ca2+递送至关重要。此外，MTDY已被证明可以控制ROS诱导的线粒体网络中ROS诱导的凋亡信号传导的传播。我们开发了使我们能够标记和跟踪单个线粒体，观察融合和裂变事件并量化线粒体网络的方法，同时监测线粒体膜电位。我们的初步研究表明，B细胞具有较高的线粒体网络活性，以频繁的融合和裂变表现出来。此外，裂变后，线粒体具有损坏的膜电位是不可逆地隔离的，这表明mTDY是一种质量控制机制。我们假设线粒体融合和裂变可以通过线粒体腹板传达葡萄糖诱导的代谢信号。诱导糖尿病的环境因素，例如糖脂肪毒性（GLT）。损害MTDV。导致线粒体功能的逐渐恶化，这表现为通过降低活性水平的线粒体的亚群的产生。我们将：（a）测试改变mTDY将影响培养物和糖尿病动物细胞中葡萄糖和GLT的B细胞反应的预测； （b）确定在B细胞中调节MTDY的因素，并确定营养参数和作为介体功能的代谢途径； （c）确定葡萄糖刺激的胰岛素分泌过程中mTDY在钙递送至线粒体中的作用，以及在GLT下B细胞内线粒体种群的损伤修复和质量控制。这项研究探讨了糖尿病的机制。它将为其病理生理学检验新的假设，并确定潜在的糖尿病，肥胖和代谢综合征的药物靶标。