Mitochondrial dynamics in beta cell function and dysfunction

描述(申请人提供)：线粒体作为b细胞营养整合因子起着关键作用。糖尿病的表现之一是线粒体对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。这项研究的目的是确定在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在糖尿病b细胞模型中的最新发现，证明了每个单独细胞中出现了不活跃的线粒体亚群，并伴随着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，在b细胞中诱导融合和裂变蛋白可以防止非活性单位的出现，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)，在其他类型的细胞中已被证明对生物能量性能和整个线粒体网络的钙传递是必不可少的。此外，MtDy已被证明控制ROS诱导的细胞凋亡信号在线粒体网络中的传播。我们已经开发出方法，使我们能够标记和跟踪单个线粒体，观察融合和裂变事件，并量化线粒体网络，同时监测线粒体膜电位。我们的初步研究表明，b细胞具有高度的线粒体网络活性，表现为频繁的融合和分裂。此外，分裂后，膜电位受损的线粒体不可逆转地分离，这表明mtDy是一种质量控制机制。我们假设线粒体融合和分裂通过线粒体网络传递葡萄糖诱导的代谢信号。诱发糖尿病的环境因素，如糖脂毒性(GLT)。损害MtDv。导致线粒体功能的逐渐恶化，表现为产生活性水平降低的线粒体亚群。我们将：(A)测试在培养和糖尿病动物细胞中改变mtDy将影响b细胞对葡萄糖和GLT的反应的预测；(B)确定b细胞中调节mtDy的因素，并确定作为介体的营养参数和代谢途径；以及(C)确定mtDy在葡萄糖刺激的胰岛素分泌过程中向线粒体输送钙的作用，以及在GLT下b细胞内线粒体数量的损伤修复和质量控制中的作用。这项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说，并确定治疗糖尿病、肥胖症和代谢综合征的潜在新药靶点。

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.