Mitochondrial dynamics in beta cell function and dysfunction

线粒体作为p-细胞的营养整合因子起着关键作用。糖尿病的表现之一是 线粒体逐渐减少！对燃料的反应产生信号的能力。造成这种情况的原因是 逐渐恶化的情况目前还不清楚。本研究的目的是确定心力衰竭的机制。 线粒体退化！在p细胞功能障碍和糖尿病的发展过程中的作用。本研究 利用我们在糖尿病p细胞模型中的最新发现，展示了 每个细胞内线粒体的不活跃亚群，伴随着 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细胞中的裂变蛋白阻止不活跃单位的出现，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)，已经在其他细胞中被显示出来 类型对于生物能量的性能和整个线粒体的钙离子输送是必不可少的！网络。 此外，mtDy已被证明控制ROS诱导的细胞凋亡信号的传播。 线粒体)网络。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，并对线粒体进行量化！网络，同时监控 线粒体！膜电位。我们的初步研究表明，p细胞有很高的线粒体！ 网络活动表现为频繁的融合和裂变。此外，在分裂之后，线粒体与 受损的膜电位是不可逆的分离，这表明mtDy作为一种质量 控制机制。 我们假设线粒体！融合和裂变用于传递葡萄糖诱导的新陈代谢 通过线粒体发出信号！网络。诱发糖尿病的环境因素，如糖脂毒性 (GLT)。损害MtDv。导致线粒体逐渐退化！函数所表现出来的 产生活动水平降低的线粒体亚群。 我们将：(A)测试改变mtDy将影响p细胞对葡萄糖和GLT反应的预测 在糖尿病动物的培养和细胞中；(B)确定调节p细胞和 确定起中介作用的营养参数和代谢途径；以及(C) MtDy在葡萄糖刺激下胰岛素线粒体钙转运中的作用 分泌，以及线粒体的损伤修复和质量控制！P-cell内的种群 在GLT下。这项研究探讨了糖尿病的发病机制。它将测试一个新的假设，用于其 并确定治疗糖尿病、肥胖症和代谢综合征的潜在新药靶点。

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.