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Title: Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells

Abstract

Mitochondria form a tubular network in mammalian cells, and the mitochondrial life cycle is determined by fission, fusion and autophagy. Dynamin-related protein 1 (Drp1) has a pivotal role in these processes because it alone is able to constrict mitochondria. However, the regulation and function of Drp1 have been shown to vary between cell types. Mitochondrial morphology affects mitochondrial metabolism and function. In pancreatic beta cells mitochondrial metabolism is a key component of the glucose-induced cascade of insulin secretion. The goal of the present study was to investigate the action of Drp1 in pancreatic beta cells. For this purpose Drp1 was down-regulated by means of shDrp1 in insulin-secreting INS1 cells and mouse pancreatic islets. In INS1 cells reduced Drp1 expression resulted in diminished expression of proteins regulating mitochondrial fusion, namely mitofusin 1 and 2, and optic atrophy protein 1. Diminished mitochondrial dynamics can therefore be assumed. After down-regulation of Drp1 in INS1 cells and spread mouse islets the initially homogenous mitochondrial network characterised by a moderate level of interconnections shifted towards high heterogeneity with elongated, clustered and looped mitochondria. These morphological changes were found to correlate directly with functional alterations. Mitochondrial membrane potential and ATP generation were significantly reduced in INS1more » cells after Drp1down-regulation. Finally, a significant loss of glucose-stimulated insulin secretion was demonstrated in INS1 cells and mouse pancreatic islets. In conclusion, Drp1 expression is important in pancreatic beta cells to maintain the regulation of insulin secretion. -- Highlights: •Down-regulation of Drp1 in INS1 cells reduces mitochondrial fusion protein expression. •Mitochondrial membrane potential in INS1 cells is diminished after Drp1 down-regulation. •Mitochondria become elongated after down-regulation of Drp1 in beta cells. •Down-regulation of Drp1 in islets evokes loss of glucose-stimulated insulin secretion.« less

Authors:
; ; ;
Publication Date:
OSTI Identifier:
22598764
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 474; Journal Issue: 4; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ATP; ATROPHY; ENDOPLASMIC RETICULUM; GENE REGULATION; GLUCOSE; INSULIN; LIFE CYCLE; METABOLISM; MICE; MITOCHONDRIA; MORPHOLOGICAL CHANGES; PANCREAS; SECRETION

Citation Formats

Reinhardt, Florian, Schultz, Julia, Waterstradt, Rica, and Baltrusch, Simone. Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2016.04.142.
Reinhardt, Florian, Schultz, Julia, Waterstradt, Rica, & Baltrusch, Simone. Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells. United States. https://doi.org/10.1016/J.BBRC.2016.04.142
Reinhardt, Florian, Schultz, Julia, Waterstradt, Rica, and Baltrusch, Simone. 2016. "Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells". United States. https://doi.org/10.1016/J.BBRC.2016.04.142.
@article{osti_22598764,
title = {Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells},
author = {Reinhardt, Florian and Schultz, Julia and Waterstradt, Rica and Baltrusch, Simone},
abstractNote = {Mitochondria form a tubular network in mammalian cells, and the mitochondrial life cycle is determined by fission, fusion and autophagy. Dynamin-related protein 1 (Drp1) has a pivotal role in these processes because it alone is able to constrict mitochondria. However, the regulation and function of Drp1 have been shown to vary between cell types. Mitochondrial morphology affects mitochondrial metabolism and function. In pancreatic beta cells mitochondrial metabolism is a key component of the glucose-induced cascade of insulin secretion. The goal of the present study was to investigate the action of Drp1 in pancreatic beta cells. For this purpose Drp1 was down-regulated by means of shDrp1 in insulin-secreting INS1 cells and mouse pancreatic islets. In INS1 cells reduced Drp1 expression resulted in diminished expression of proteins regulating mitochondrial fusion, namely mitofusin 1 and 2, and optic atrophy protein 1. Diminished mitochondrial dynamics can therefore be assumed. After down-regulation of Drp1 in INS1 cells and spread mouse islets the initially homogenous mitochondrial network characterised by a moderate level of interconnections shifted towards high heterogeneity with elongated, clustered and looped mitochondria. These morphological changes were found to correlate directly with functional alterations. Mitochondrial membrane potential and ATP generation were significantly reduced in INS1 cells after Drp1down-regulation. Finally, a significant loss of glucose-stimulated insulin secretion was demonstrated in INS1 cells and mouse pancreatic islets. In conclusion, Drp1 expression is important in pancreatic beta cells to maintain the regulation of insulin secretion. -- Highlights: •Down-regulation of Drp1 in INS1 cells reduces mitochondrial fusion protein expression. •Mitochondrial membrane potential in INS1 cells is diminished after Drp1 down-regulation. •Mitochondria become elongated after down-regulation of Drp1 in beta cells. •Down-regulation of Drp1 in islets evokes loss of glucose-stimulated insulin secretion.},
doi = {10.1016/J.BBRC.2016.04.142},
url = {https://www.osti.gov/biblio/22598764}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 4,
volume = 474,
place = {United States},
year = {Fri Jun 10 00:00:00 EDT 2016},
month = {Fri Jun 10 00:00:00 EDT 2016}
}