Mediators of mitophagy in the regulation of beta cell function

线粒体自噬调节β细胞功能的介质

• 批准号: 9237051
• 负责人: Scott Soleimanpour
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237051
• 关键词: Anabolism; Area; Autophagosome; Beta Cell; Binding; Bioenergetics; Biogenesis; Blood Glucose; C-terminal; Cell physiology; Cells; Cellular biology; Characteristics; Chronic Disease; Confocal Microscopy; Data; Defect; Diabetes Mellitus; Diabetes prevention; Diet; Disease; Ensure; Equilibrium; Evaluation; Failure; Financial compensation; Functional disorder; Genes; Genetic; Genetic Polymorphism; Goals; Health; Homeostasis; Human; Impairment; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Lead; Lysosomes; Mediating; Mediator of activation protein; Mitochondria; Modeling; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pathogenesis; Pathway interactions; Patients; Peripheral; Physiological; Power Plants; Prevention; Process; Protein Isoforms; Proteins; Proteomics; Publishing; RNA Splicing; Regulation; Reporting; Respiration; Respiratory physiology; Role; Sentinel; Structure; Susceptibility Gene; Testing; biochemical model; blood glucose regulation; cell type; diabetic; fitness; insulin secretion; islet; meetings; mitochondrial autophagy; mitochondrial dysfunction; mouse model; novel; parkin gene/protein; prevent; secretion process; ubiquitin-protein ligase

ABSTRACT Diabetes results from insufficient functional β-cell mass to meet peripheral insulin demands. β-cells rely upon mitochondrial respiration to generate the energy necessary for insulin biosynthesis, processing, and secretion. Indeed, defects in mitochondrial structure and function have been reported in the β-cells of patients with type 2 diabetes. Defects in mitochondrial structure and function are characteristic of impairments in mitophagy, a selective form of mitophagy necessary for elimination of dysfunctional mitochondria; however, the role of mitophagy in type 2 diabetes pathogenesis is not well understood. We previously discovered a key role for the diabetes susceptibility gene Clec16a in control of glucose homeostasis in humans and mice through its regulation of β-cell mitophagy. Therefore, our goal is to dissect the mechanistic and physiologic regulation of Clec16a-mediated mitophagy in β-cells to elucidate its contribution to diabetes pathogenesis. The central hypothesis to be tested is that disruption of Clec16a regulation of its key effectors, the E3 ubiquitin ligase Nrdp1 and the Nrdp1 target Parkin, contribute to β-cell failure in type 2 diabetes. We will test this hypothesis by the following approach: Specific Aim 1 will directly assess the mechanistic implications of Clec16a disease polymorphisms that alter its functional domains. Specific Aim 2 will determine if the mitophagy initiator Parkin, which recognizes unhealthy mitochondria during mitophagy, serves as the primary downstream effector of Clec16a in β-cell mitophagy. Specific Aim 3 will delineate the role of Clec16a during β-cell compensation for diet-induced obesity and in human islets from type 2 diabetic donors. We anticipate obtaining a clear understanding of the importance and translational relevance of mitophagy in β-cell function from an evaluation of the central effectors crucial to the disposal of unhealthy mitochondria. These results should advance the field of β-cell biology by defining the role of mitophagy in type 2 diabetes pathogenesis and could open new horizons for therapies for patients with diabetes.

摘要 糖尿病是由于功能性β细胞质量不足以满足外周胰岛素需求而引起的。β细胞依赖于 线粒体呼吸产生胰岛素生物合成、加工和分泌所需的能量。 事实上，在2型糖尿病患者的β细胞中已经报道了线粒体结构和功能的缺陷。 糖尿病线粒体结构和功能的缺陷是线粒体自噬受损的特征， 选择性形式的线粒体自噬必要的消除功能障碍的线粒体;然而， 线粒体自噬在2型糖尿病发病机制中的作用尚不清楚。我们以前发现了一个关键作用， 糖尿病易感基因Clec 16 a在人类和小鼠中通过其对葡萄糖代谢的调节作用 β细胞自噬的调节。因此，我们的目标是剖析的机制和生理调节， Clec 16 a介导的β细胞线粒体自噬，以阐明其对糖尿病发病机制的贡献。中央 待检验假设是Clec 16 a对其关键效应物E3泛素连接酶的调节的破坏 Nrdp 1和Nrdp 1靶向Parkin，导致2型糖尿病中β细胞衰竭。我们将通过以下方式检验这一假设： 具体目标1将直接评估Clec 16 a疾病的机制影响 多态性改变其功能结构域。具体目标2将确定是否线粒体自噬发起者帕金， 在线粒体自噬过程中识别不健康的线粒体，作为主要的下游效应物， Clec 16 a在β细胞线粒体自噬中的作用具体目标3将描述Clec 16 a在β细胞代偿过程中的作用， 饮食诱导的肥胖和2型糖尿病供体的人类胰岛中。我们预计会得到一个明确的 从评价中理解线粒体自噬在β细胞功能中的重要性和翻译相关性 对处理不健康的线粒体至关重要的中央效应器。这些结果将推动 通过定义线粒体自噬在2型糖尿病发病机制中的作用， 糖尿病患者的治疗前景。