Control of insulin secretion by mitochondrial fusion

摘要 糖尿病是由于功能性β细胞群不足以满足外周胰岛素需求所致。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型患者的β细胞中已经报告了线粒体结构和功能的缺陷 糖尿病(T2D)。线粒体结构和功能缺陷是线粒体损伤的特征 动力学，线粒体网络的融合和分裂的平衡。线粒体融合受以下因素支配 几种动力素样GTP酶，包括Mitofusins 1和2(Mfn1和2)。Mfn1和/或Mfn2的表达为 人T2D胰岛、小鼠T2D模型的减少，以及有毒胰岛淀粉样蛋白的沉积 多肽低聚物。然而，Mfn1和Mfn2在体内β-细胞中的功能及其在T2D中的作用 发病机制尚不清楚。因此，我们的目标是剖析生物力学和生理调节的机制。 线粒体在β-细胞中的融合以阐明其在糖尿病发病机制中的作用。核心假设是 Mfn1和Mfn2通过控制线粒体调节胰岛素分泌和胰岛β细胞连接 DNA和网络的稳定性以及它们的失调导致了β细胞在T2D中的失败。我们将检验这一假设 通过以下方法：特定目标1将直接评估线粒体丢失的机制含义 融合对线粒体DNA拷贝数的控制。具体目标2将勾勒出 在线粒体融合受损后，胰岛素可恢复胰岛素分泌。《特定目标3》将展开调查 丝裂原蛋白在人β细胞中的重要性。我们期望得到一个清楚的了解 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器。这些结果将推动β-CELL领域的发展 通过确定线粒体融合在T2D发病机制中的作用并可能开辟新的视野 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.