Control of insulin secretion by mitochondrial fusion

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（T2 D）。线粒体结构和功能的缺陷是线粒体损伤的特征。 动力学，线粒体网络融合和裂变的平衡。线粒体融合由 几种动力蛋白样GTP酶，包括线粒体融合蛋白1和2（Mfn 1和2）。Mfn 1和/或Mfn 2的表达是 在人T2 D胰岛、T2 D小鼠模型中以及在毒性胰岛淀粉样蛋白沉积后减少 多肽寡聚体。然而，Mfn 1和Mfn 2在体内β细胞中的功能，以及它们在T2 D中的作用， 发病机制尚不清楚。因此，我们的目标是剖析的机制和生理调节， 图1示出了在β细胞中的线粒体融合以阐明其对糖尿病发病机制的贡献。核心假设是 Mfn 1和2通过控制线粒体膜电位来调节胰岛素分泌和胰岛β细胞连接， DNA和网络稳定性及其失调导致T2 D中的β细胞衰竭。我们将检验这一假设 具体目标1将直接评估线粒体缺失的机制影响， 融合对线粒体DNA拷贝数的控制。具体目标2将描述 肠促胰岛素在线粒体融合受损后恢复胰岛素分泌。第3章调查 线粒体融合蛋白在人类β细胞中的重要性。我们期待着获得一个清晰的理解， 线粒体融合在β细胞功能中的重要性和翻译相关性， 对维持线粒体结构至关重要的效应子。这些结果将推动β细胞研究领域的发展 生物学通过定义线粒体融合在T2 D发病机制中的作用，可以为 糖尿病患者的治疗方法。

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.