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: 8373586
• 负责人: BARBARA E. CORKEY
• 金额: $ 40.98万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373586
• 关键词: Address; Autophagocytosis; Beta Cell; Bypass; Carbohydrates; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Characteristics; Chimeric Proteins; Cytoprotection; Data; Defense Mechanisms; Development; Diabetes Mellitus; Diabetes prevention; Diet; Disease model; Down-Regulation; Environment; Equilibrium; Esterification; Event; Fatty acid glycerol esters; Functional disorder; Glucose; Grant; Hyperglycemia; In Vitro; Insulin; Intervention; Lead; Life Cycle Stages; Link; Lipids; Lipolysis; Measures; Mediating; Mitochondria; Modeling; Molecular; Mus; Neurons; Nutrient; Obesity; Pathway interactions; Pattern; Permeability; Phase; Phosphotransferases; Play; Population; Prevention; Process; Production; Proteins; Reactive Oxygen Species; Research Support; Resistance; Respiration; Role; Streptozocin; Time; Ubiquitination; diabetic; impaired glucose tolerance; improved; in vivo; inhibitor/antagonist; insulin secretion; islet; knock-down; lipid metabolism; mutant; new therapeutic target; novel; oxidation; parkin gene/protein; prevent; research study; response; stem; therapeutic target; ubiquitin isopeptidase

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. PUBLIC HEALTH RELEVANCE: The ability of the majority of the population to adapt to the obese state and not develop impaired glucose tolerance suggests the existence of compensatory mechanisms. This proposal stems from our recent identification of a molecular event that results in the protection of the insulin producing cells and allows for enhanced insulin secretion. Experiments proposed in this study will help decipher the beneficial from the detrimental processes within the adaptive response, thereby allowing for the identification of therapeutic targets for the prevention of diabetes.

描述（由申请人提供）：营养诱导的β细胞功能障碍和死亡被认为在糖尿病的发展中发挥着核心作用。 对高脂肪和碳水化合物环境（HFC）做出反应的致病和防御机制可能提供有价值的治疗靶点。 该资助支持的研究将线粒体融合裂变和自噬确定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，导致线粒体网络完全断裂并通过线粒体自噬刺激线粒体周转。初步的体内和体外数据表明，碎片化是由 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 Mfn2 的体内缺失或体外敲低会导致解偶联增加、ROS 减少和细胞活力保护。这些有益效果是以胰岛素分泌失调为代价的，表现为基础分泌增加、第一相减少、第二相增加和振荡模式减弱。我们假设 HFC 诱导的胰岛 Mfn2 降解和随之而来的网络破碎可以作为一种补偿机制来保护 细胞活力，同时解除胰岛素分泌的调节。我们将通过以下目标来解决这一假设：Aim1 将确定 Mfn2 更新在预防 ¿-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 周转对 HFC 诱导的胰岛素分泌失调的贡献以及 Mfn2 调节分泌的机制。 Aim3 将研究 ¿ 细胞中控制 Mfn2 更新的机制。我们的初步研究已经确定了一种刺激 Mfn2 周转的新机制，我们能够通过药理学激活该机制。 我们将评估这种新的治疗靶点作为诱导适应的机制。揭示调节 Mfn2 周转双重效应的途径将有助于设计干预措施，在维持有益效果的同时抑制有害作用。 公共卫生相关性：大多数人群适应肥胖状态且不出现糖耐量受损的能力表明存在补偿机制。该提议源于我们最近发现的一种分子事件，该事件可保护胰岛素生成细胞并增强胰岛素水平 分泌。本研究中提出的实验将有助于解读适应性反应中的有益过程和有害过程，从而确定预防糖尿病的治疗靶点。