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Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion

Wollam, Joshua and Mahata, Sumana and Riopel, Matthew and Hernandez-Carretero, Angelina and Biswas, Angshuman and Bandyopadhyay, Gautam K. and Chi, Nai-Wen and Eiden, Lee E. and Mahapatra, Nitish R. and Corti, Angelo and Webster, Nicholas J. G. and Mahata, Sushil K. (2017) Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion. Cell and Tissue Research, 368 (3). pp. 487-501. ISSN 0302-766X. doi:10.1007/s00441-017-2580-5.

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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 in Chga-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 that Chga-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, Cyc1 and Atp5o). These changes in secretory vesicles and the mitochondria likely contribute to the increased glucose-stimulated insulin secretion observed in Chga-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.

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Additional Information:© 2017 Springer-Verlag Berlin Heidelberg. Received: 13 December 2016; Accepted: 16 January 2017; First Online: 20 February 2017. Transmission electron microscopy was conducted at the Cellular & Molecular Medicine Electron Microscopy Core Facility at UCSD. Mahata’s home equity loan and VMRF’s bridge funding supported this work. The Noland Scholarship from Caltech supported SM. Joshua Wollam and Sumana Mahata contributed equally to this work. Compliance with ethical standards. The authors declare that they have no conflict of interest.
Funding AgencyGrant Number
Veterans Medical Research FoundationUNSPECIFIED
Subject Keywords:Insulin; Glucagon; Somatostatin; Chromogranin A; Pancreastatin; Catestatin; Dense core vesicle; Mitochondria
Issue or Number:3
Record Number:CaltechAUTHORS:20170227-094103010
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Official Citation:Wollam, J., Mahata, S., Riopel, M. et al. Cell Tissue Res (2017) 368: 487. doi:10.1007/s00441-017-2580-5
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74542
Deposited By: Tony Diaz
Deposited On:27 Feb 2017 17:55
Last Modified:11 Nov 2021 05:28

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