Control of insulin secretion by mitochondrial fusion

通过线粒体融合控制胰岛素分泌

基本信息

批准号：
10753730
负责人：
Brett A Kaufman
金额：
$ 63.79万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-23 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753730
关键词：
Affect Agonist Anabolism Area Beta Cell Blood Glucose Cell physiology Cells Cellular biology Characteristics Chronic Disease DNA copy number Data Defect Deposition Diabetes Mellitus Diabetes prevention Diabetic mouse Dynamin Equilibrium Evaluation Exhibits Exposure to Failure Functional disorder Gene Dosage Glucose Intolerance Goals Guanosine Triphosphate Phosphohydrolases Health Homeostasis Human Impairment Induced Mutation Insulin Link Maintenance Mediating Membrane Metabolic Mitochondria Mitochondrial DNA Mitochondrial Matrix Mitochondrial RNA Modeling Non-Insulin-Dependent Diabetes Mellitus Pancreas Pathogenesis Pathway interactions Patients Peptide Hydrolases Peripheral Physiological Ploidies Pluripotent Stem Cells Power Plants Prediabetes syndrome Production Publishing Regulation Reporting Respiration Risk Role Signal Transduction Stress Structural defect Structure Testing Tissues Xenograft Model blood glucose regulation diabetes pathogenesis high resolution imaging imaging approach improved in vivo insight insulin secretion islet islet amyloid polypeptide metabolomics mitochondrial dysfunction mitochondrial membrane mouse model novel novel therapeutics optogenetics overexpression pharmacologic posttranscriptional prevent restoration superresolution imaging

Affect Agonist Anabolism Area Beta Cell Blood Glucose Cell physiology Cells Cellular biology Characteristics Chronic Disease DNA copy number Data Defect Deposition Diabetes Mellitus Diabetes prevention Diabetic mouse Dynamin Equilibrium Evaluation Exhibits Exposure to Failure Functional disorder Gene Dosage Glucose Intolerance Goals Guanosine Triphosphate Phosphohydrolases Health Homeostasis Human Impairment Induced Mutation Insulin Link Maintenance Mediating Membrane Metabolic Mitochondria Mitochondrial DNA Mitochondrial Matrix Mitochondrial RNA Modeling Non-Insulin-Dependent Diabetes Mellitus Pancreas Pathogenesis Pathway interactions Patients Peptide Hydrolases Peripheral Physiological Ploidies Pluripotent Stem Cells Power Plants Prediabetes syndrome Production Publishing Regulation Reporting Respiration Risk Role Signal Transduction Stress Structural defect Structure Testing Tissues Xenograft Model blood glucose regulation diabetes pathogenesis high resolution imaging imaging approach improved in vivo insight insulin secretion islet islet amyloid polypeptide metabolomics mitochondrial dysfunction mitochondrial membrane mouse model novel novel therapeutics optogenetics overexpression pharmacologic posttranscriptional prevent restoration superresolution imaging

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项目摘要

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 (T2D). Defects in mitochondrial structure and function are characteristic of impairments in mitochondrial dynamics, the balance of fusion and fission of mitochondrial networks. Mitochondrial fusion is governed by several dynamin-like GTPases, including Mitofusins 1 and 2 (Mfn1 and 2). Expression of Mfn1 and/or Mfn2 are reduced in human T2D islets, mouse models of T2D, and following the deposition of toxic islet amyloid polypeptide oligomers. However, the functions of Mfn1 and Mfn2 in β-cells in vivo, and their role in T2D pathogenesis are unclear. Therefore, our goal is to dissect the mechanistic and physiologic regulation of mitochondrial fusion in β-cells to elucidate its contribution to diabetes pathogenesis. The central hypothesis to be tested is that Mfn1 and 2 regulate insulin secretion and islet β-cell connectivity through control of mitochondrial DNA and network stability, and their dysregulation contribute to β-cell failure in T2D. We will test this hypothesis by the following approach: Specific Aim 1 will directly assess the mechanistic implications of loss of mitochondrial fusion on control of mitochondrial DNA copy number. Specific Aim 2 will delineate the mechanisms by which incretins restore insulin secretion following impairments in mitochondrial fusion. Specific Aim 3 will investigate the importance of mitofusins within human β-cells. We anticipate obtaining a clear understanding of the importance and translational relevance of mitochondrial fusion in β-cell function from an evaluation of the central effectors crucial to the maintenance of mitochondrial structure. These results should advance the field of β-cell biology by defining the role of mitochondrial fusion in T2D pathogenesis and could open new horizons for therapies for patients with diabetes.

抽象的糖尿病是由于功能性β细胞质量不足而导致的，无法满足外周胰岛素需求。 β细胞依靠线粒体呼吸产生胰岛素生物合成，加工和分泌所需的能量。实际上，在2型患者的β细胞中已经报道了线粒体结构和功能的缺陷糖尿病（T2D）。线粒体结构和功能的缺陷是线粒体损伤的特征动力学，线粒体网络的融合和裂变的平衡。线粒体融合受几种动力蛋白样的GTPase，包括丝线Fusins 1和2（MFN1和2）。 MFN1和/或MFN2的表达是在人类T2D胰岛，T2D的小鼠模型中减少了，有毒胰岛淀粉样蛋白的沉积后多肽低聚物。但是，MFN1和MFN2在体内的功能及其在T2D中的作用发病机理不清楚。因此，我们的目标是剖析 β细胞中的线粒体融合，以阐明其对糖尿病发病机理的贡献。中心假设接受测试是MFN1和2通过控制线粒体调节胰岛素分泌和胰岛β细胞连接性 DNA和网络稳定性及其失调导致T2D中的β细胞衰竭。我们将检验这个假设通过以下方法：特定目标1将直接评估线粒体丧失的机理含义融合线粒体DNA拷贝数。具体目标2将描述其通过的机制线粒体融合的损伤后，肠降量恢复胰岛素分泌。具体目标3将调查介脂蛋白在人β细胞中的重要性。我们预计对线粒体融合在β细胞功能中的重要性和翻译相关性，对中央的评估效应子对维持线粒体结构至关重要。这些结果应推进β细胞的领域生物学通过定义线粒体融合在T2D发病机理中的作用，并可以为糖尿病患者的疗法。