Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion.
Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion.
复制标题
嗜铬粒蛋白 A 调节囊泡储存和线粒体动力学，从而影响胰岛素分泌。
DOI：
10.1007/s00441-017-2580-5
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发表时间：
2017
影响因子：
3.6
通讯作者：
Mahata,SushilK
中科院分区：
文献类型：
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作者：
Wollam,Joshua;Mahata,Sumana;Riopel,Matthew;Hernandez-Carretero,Angelina;Biswas,Angshuman;Bandyopadhyay,GautamK;Chi,Nai-Wen;Eiden,LeeE;Mahapatra,NitishR;Corti,Angelo;Webster,NicholasJG;Mahata,SushilK
嗜铬粒蛋白A(Chromoranin A，CGA)是神经内分泌组织中调节分泌途径的一种前激素和粒细胞因子。在胰腺内分泌的β细胞中，CgA是胰岛素分泌囊泡的主要载体。CGA缺乏对胰岛素囊泡形成和胞吐的影响尚不清楚。此外，目前还没有关于环丙沙星对β-细胞线粒体功能影响的文献。使用三种不同的抗体，我们证明了CGA在胰岛细胞中被加工成含有血管抑素和儿茶素的片段。Chga-KO胰岛CGA缺乏导致嗜铬粒蛋白B、分泌颗粒素II、SNARE蛋白和胰岛素基因的代偿性过度表达，以及胰岛素蛋白含量的增加。胰岛超微结构研究表明，与野生型(WT)对照相比，CHGA-KOβ-细胞含有较少的未成熟分泌颗粒，但较多的成熟分泌颗粒和与质膜对接的小泡。与对照相比，CgA缺陷的β细胞线粒体体积、数密度和融合增加，核编码基因(Ndufa9、Ndufs8、Cyc1和Atp50)表达增加。分泌囊泡和线粒体的这些变化可能是在Chga-KO小鼠中观察到的葡萄糖刺激的胰岛素分泌增加的原因。我们的结论是，CgA是协调线粒体动力学、分泌囊泡量子和GSI以优化β-细胞分泌功能的重要调节因子，这表明线粒体融合与GSIS之间存在着强烈的、依赖于CgA的正向联系。
Chromogranin A (CgA) is a prohormone and a granulogenic factor that regulates secretory pathways in neuroendocrine tissues. In β-cells of the endocrine pancreas, CgA is a major cargo in insulin secretory vesicles. The impact of CgA deficiency on the formation and exocytosis of insulin vesicles is yet to be investigated. In addition, no literature exists on the impact of CgA on mitochondrial function in β-cells. Using three different antibodies, we demonstrate that CgA is processed to vasostatin- and catestatin-containing fragments in pancreatic islet cells. CgA deficiency inChga-KO islets leads to compensatory overexpression of chromogranin B, secretogranin II, SNARE proteins and insulin genes, as well as increased insulin protein content. Ultrastructural studies of pancreatic islets revealed thatChga-KO β-cells contain fewer immature secretory granules than wild-type (WT) control but increased numbers of mature secretory granules and plasma membrane-docked vesicles. Compared to WT control, CgA-deficient β-cells exhibited increases in mitochondrial volume, numerical densities and fusion, as well as increased expression of nuclear encoded genes (Ndufa9,Ndufs8,Cyc1andAtp5o). These changes in secretory vesicles and the mitochondria likely contribute to the increased glucose-stimulated insulin secretion observed inChga-KO mice. We conclude that CgA is an important regulator for coordination of mitochondrial dynamics, secretory vesicular quanta and GSIS for optimal secretory functioning of β-cells, suggesting a strong, CgA-dependent positive link between mitochondrial fusion and GSIS.