Mitochondrial dynamics in beta cell function and dysfunction

描述（由申请人提供）：营养诱导的细胞功能障碍和死亡被认为在糖尿病的发展中起着核心作用。高脂肪和高碳水化合物环境（HFC）的致病和防御机制可能提供有价值的治疗靶点。该基金支持的研究确定了线粒体融合-裂变和自噬是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断裂，并通过线粒体自噬刺激线粒体更新。体内和体外初步数据表明，断裂是由hfc诱导的线粒体融合蛋白Mfn2降解介导的。值得注意的是，我们发现体内缺失或体外敲低Mfn2会导致解偶联增加，ROS降低和保护细胞活力。这些有益的影响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，振荡模式减弱。我们假设hfc诱导的胰岛Mfn2降解和随后的网络分裂作为一种补偿机制保护了细胞活力，同时解除了胰岛素分泌的调节。我们将通过以下目的来解决这一假设：目的1将确定Mfn2转换在预防-细胞损失中的作用，并将评估Mfn2下调作为糖尿病模型治疗靶点的潜在用途。Aim2将确定Mfn2转换对hfc诱导的胰岛素分泌失调的贡献，以及Mfn2调节胰岛素分泌的机制。Aim3将研究在细胞中控制Mfn2转换的机制。我们的初步研究已经确定了一种刺激Mfn2周转的新机制，我们已经能够从药理学上激活。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Mfn2转换的双重效应的途径将允许设计干预措施，在抑制有害影响的同时保持有益效果。

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.