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Non-canonical roles of Bcl-xL in regulating mitochondrial function and morphology in pancreatic beta-cells Shi, Rocky Qiushi
Abstract
Glucose-stimulated insulin secretion from pancreatic β-cells depends on mitochondrial oxidative metabolism. Mitochondrial dysfunction is believed to be a significant factor in the development of type 2 diabetes (T2D). Mitochondria exist as dynamic networks and the control of mitochondrial biomass and fusion/fission dynamics is essential for cellular health and function. The anti-apoptotic protein Bcl-xL has recently been demonstrated to dampen β-cell mitochondrial metabolism and studies in other cell types suggest Bcl-xL regulates mitochondrial biomass and dynamics. We hypothesize that Bcl-xL is important for β-cell adaptation to metabolic stress by regulating mitochondrial dynamics and mass. To quantitatively study mitochondrial structural changes, we developed an image analysis pipeline for 2D/3D confocal imaging of mitochondria in FIJI. We applied the pipeline to primary islet cells and found that glucose stimulation is correlated with a more fragmented mitochondrial morphology. In vitro Bcl-xL overexpression causes β-cell mitochondria to lose their tubular network structure and aggregate. These changes to network morphology and kinetics are associated with decreased total mitochondrial volume and a marked impairment of β-cell O2 consumption. β-cell specific Bcl-xL knockout islet cells demonstrated increased basal activity and decreased average mitochondrion size, suggesting that they behave more similarly to β-cells undergoing glucose stimulation. Challenging β-cells with prolonged high glucose culture increased the size and overall connectivity of their mitochondrial network. In Bcl-xL knockout β-cells this increase in total mitochondrial mass and networking was significantly amplified, but was associated with reduced morphological and functional glucose-responsiveness of the individual mitochondrion. In conclusion, our in vitro data demonstrate that Bcl-xL affects mitochondrial networking, function, and adaptation to stress in pancreatic β-cells.
Item Metadata
Title |
Non-canonical roles of Bcl-xL in regulating mitochondrial function and morphology in pancreatic beta-cells
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2018
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Description |
Glucose-stimulated insulin secretion from pancreatic β-cells depends on mitochondrial oxidative metabolism. Mitochondrial dysfunction is believed to be a significant factor in the development of type 2 diabetes (T2D). Mitochondria exist as dynamic networks and the control of mitochondrial biomass and fusion/fission dynamics is essential for cellular health and function. The anti-apoptotic protein Bcl-xL has recently been demonstrated to dampen β-cell mitochondrial metabolism and studies in other cell types suggest Bcl-xL regulates mitochondrial biomass and dynamics. We hypothesize that Bcl-xL is important for β-cell adaptation to metabolic stress by regulating mitochondrial dynamics and mass. To quantitatively study mitochondrial structural changes, we developed an image analysis pipeline for 2D/3D confocal imaging of mitochondria in FIJI. We applied the pipeline to primary islet cells and found that glucose stimulation is correlated with a more fragmented mitochondrial morphology. In vitro Bcl-xL overexpression causes β-cell mitochondria to lose their tubular network structure and aggregate. These changes to network morphology and kinetics are associated with decreased total mitochondrial volume and a marked impairment of β-cell O2 consumption. β-cell specific Bcl-xL knockout islet cells demonstrated increased basal activity and decreased average mitochondrion size, suggesting that they behave more similarly to β-cells undergoing glucose stimulation. Challenging β-cells with prolonged high glucose culture increased the size and overall connectivity of their mitochondrial network. In Bcl-xL knockout β-cells this increase in total mitochondrial mass and networking was significantly amplified, but was associated with reduced morphological and functional glucose-responsiveness of the individual mitochondrion. In conclusion, our in vitro data demonstrate that Bcl-xL affects mitochondrial networking, function, and adaptation to stress in pancreatic β-cells.
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Genre | |
Type | |
Language |
eng
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Date Available |
2018-05-01
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0366141
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2018-09
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International