Mitochondrial dynamics in beta cell function and dysfunction

描述（由申请人提供）：营养素诱导的细胞功能障碍和死亡被认为在糖尿病的发展中起核心作用。 对高脂肪和碳水化合物环境（HFC）作出反应的致病和防御机制可能提供有价值的治疗靶标。 这项资助支持的研究建立了线粒体融合-裂变和自噬作为形成线粒体生命周期的相关事件。此外，我们确定HFC通过阻止线粒体融合来阻止线粒体生命周期，导致线粒体网络的完全碎片化和线粒体自噬刺激线粒体周转。初步的体内和体外数据表明，碎片介导的HFC诱导的线粒体融合蛋白，Mfn 2的降解。 值得注意的是，我们发现Mfn 2的体内缺失或体外敲低导致解偶联增加，ROS减少和对细胞活力的保护。这些有益的效果是以胰岛素分泌失调为代价的，表现为基础分泌增加、第一阶段减少、第二阶段增加和振荡模式钝化。我们假设HFC诱导的胰岛Mfn 2的降解和随后的网络碎片作为一种补偿机制来保护细胞活力，同时解除对胰岛素分泌的调节。我们将通过以下目的来解决这一假设：目的1将确定Mfn 2周转在预防细胞损失中的作用，并将评估Mfn 2下调作为糖尿病模型治疗靶点的潜在用途。Aim 2将确定Mfn 2周转对HFC诱导的胰岛素分泌失调的贡献以及Mfn 2调节分泌的机制。Aim 3将研究Mfn 2周转在细胞中控制的机制。我们的初步研究已经确定了一种新的机制，刺激Mfn 2营业额，我们已经能够激活ESTA。 我们将评估这种新的治疗靶点作为诱导适应的机制。揭示介导Mfn 2周转双重效应的途径将允许设计干预措施，以保持有益效果，同时抑制有害作用。

DESCRIPTION (provided by applicant): Nutrient-induced ¿-cell dysfunction and death are thought to play a central role in the development of diabetes. Pathogenic and defense mechanisms that respond to a high fat and carbohydrate environment (HFC) may provide valuable therapeutic targets. Research supported by this grant established mitochondrial fusion-fission and autophagy as linked events that form the mitochondrial life cycle. Furthermore we determined that HFC arrests the mitochondrial life cycle by preventing mitochondrial fusion, leading to the complete fragmentation of the mitochondrial network and stimulation of mitochondrial turnover by mitophagy. Preliminary in vivo and in vitro data indicate that fragmentation is mediated by HFC-induced degradation of the mitochondrial fusion protein, Mfn2. Remarkably, we find that in vivo deletion or in vitro knockdown of Mfn2 leads to increased uncoupling, decreased ROS and protection of ¿-cell viability. These beneficial effects come at the expense of deregulated insulin secretion, manifested by increased basal secretion, decreased 1st phase, increased 2nd phase and a blunted oscillatory pattern. We hypothesize that HFC-induced degradation of islet Mfn2 and the ensuing network fragmentation serves to protect ¿-cell viability as a compensatory mechanism while at the same time deregulating insulin secretion. We will address this hypothesis through the following Aims: Aim1 will determine the role of Mfn2 turnover in the prevention of ¿-cell loss and will evaluate the potential use of Mfn2 downregulation as a therapeutic target in diabetic models. Aim2 will determine the contribution of Mfn2 turnover to HFC-induced deregulation of insulin secretion and the mechanism by which Mfn2 modulates secretion. Aim3 will investigate the mechanism by which Mfn2 turnover is controlled in the ¿-cell. Our preliminary studies have identified a novel mechanism for the stimulation of Mfn2 turnover which we have been able to activate pharmacologically. We will evaluate this novel therapeutic target as a mechanism to induce adaptation. Revealing the pathways that mediate the dual effects of Mfn2 turnover will allow for the devise of interventions that will maintain the beneficial effect while suppressing the detrimental.