Mediators of mitophagy in the regulation of beta cell function

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。线粒体结构和功能缺陷是吞丝分裂障碍的特征， 选择性形式的有丝分裂是消除功能障碍的线粒体所必需的；然而， 有丝分裂在2型糖尿病发病机制中的作用还不是很清楚。我们之前发现了一个关键角色 糖尿病易感基因Clec16a通过其基因调控人和小鼠的血糖稳态 β细胞有丝分裂的调控。因此，我们的目标是剖析生物力学和生理调节的机制。 Clec16a介导的β细胞有丝分裂吞噬作用，以阐明其在糖尿病发病机制中的作用。中环 有待检验的假设是，Clec16a对其关键效应物E3泛素连接酶的调节受到干扰 Nrdp1和Nrdp1靶标PARKIN导致2型糖尿病的β细胞衰竭。我们将通过以下方式验证这一假设 以下方法：具体目标1将直接评估Clec16a病的机制影响 改变其功能域的多态现象。特定目标2将确定吞噬有丝分裂的发起者帕金， 在有丝分裂过程中识别不健康的线粒体，是主要的下游效应器 Clec16a在β细胞有丝分裂吞噬中的表达。具体目标3将描述Clec16a在β-细胞代偿过程中的作用 饮食诱导的肥胖和来自2型糖尿病捐赠者的人类胰岛。我们期待着得到一个明确的 从一项评估看有丝分裂在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枢效应器。这些结果应该会推动 通过确定有丝分裂在2型糖尿病发病机制中的作用来研究β-细胞生物学领域，并可能打开新的 糖尿病患者治疗的地平线。

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.