title: Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion.
abstract: 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.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Wollam
authors.affiliation: Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
authors.forename: Sumana
authors.initials: S
authors.lastname: Mahata
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Riopel
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Angelina
authors.initials: A
authors.lastname: Hernandez-Carretero
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Angshuman
authors.initials: A
authors.lastname: Biswas
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Gautam K
authors.initials: GK
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.|VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Nai-Wen
authors.initials: NW
authors.lastname: Chi
authors.affiliation: Section on Molecular Neuroscience, NIMH-IRP, Bethesda, MD, USA.
authors.forename: Lee E
authors.initials: LE
authors.lastname: Eiden
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036, India.
authors.forename: Nitish R
authors.initials: NR
authors.lastname: Mahapatra
authors.affiliation: IRCCS San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.|VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Nicholas J G
authors.initials: NJG
authors.lastname: Webster
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA. smahata@ucsd.edu.|VA San Diego Healthcare System, San Diego, CA, USA. smahata@ucsd.edu.|Metabolic Physiology & Ultrastructural Biology Laboratory, Department of Medicine, University of California, San Diego (0732), 9500 Gilman Drive, La Jolla, CA, 92093-0732, USA. smahata@ucsd.edu.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
mesh_terms: D000818:Animals; D037282:Calreticulin / Q000378:metabolism; D002454:Cell Differentiation; D053379:Chromogranin A / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D005089:Exocytosis; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D063154:Mitochondrial Dynamics / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D022142:Secretory Vesicles
chemical_list: D037282:Calreticulin; D053379:Chromogranin A; D007328:Insulin; D010446:Peptide Fragments; C109084:chromogranin A (344-364); C121986:vasostatin; D005947:Glucose
keywords: Catestatin; Chromogranin A; Dense core vesicle; Glucagon; Insulin; Mitochondria; Pancreastatin; Somatostatin