Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Groschner, L.
METABOLISM-SECRETION COUPLING AND MITOCHONDRIAL CALCIUM ACTIVITIES IN PANCREATIC ¿ETA-CELLS
[ Diplomarbeit ] Medical University of Graz; 2013. pp. 58
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Graier Wolfgang
- Malli Roland
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- Abstract:
- Pancreatic ß-cells are the only cells capable of lowering blood glucose by secreting insulin. The ß-cell continuously adjusts its secretory activity to substrate availability in order to keep blood glucose levels within the physiological range ¿ a process referred to as metabolism-secretion coupling. Glucose is readily taken up by the ß-cell and broken down into intermediates that fuel oxidative metabolism inside the mitochondria to generate ATP. The resulting increase in the ATP/ADP ratio causes closure of plasma membrane KATP-channels, thereby depolarizing the cell and triggering the opening of voltage-gated Ca2+ channels. Consequential oscillations of cytosolic Ca2+ not only mediate the exocytosis of insulin granules, but are also relayed to other subcellular compartments including the mitochondria, where Ca2+ might act to accelerate mitochondrial metabolism in response to nutrient stimulation. The aim of this study was to investigate the role of two proteins involved in the uptake of Ca2+ by the mitochondria, mitochondrial Ca2+ uptake 1 (MICU1) and mitochondrial Ca2+ uniporter (MCU), in metabolism-secretion coupling of the pancreatic ß-cell. Employing an RNAi-mediated gene silencing strategy, I could selectively suppress the expression of MICU1 and MCU in INS-1 832/13 clonal pancreatic ß-cells. Silencing of MICU1 and MCU significantly reduced mitochondrial Ca2+ signals after stimulation with glucose. Cells deficient of MICU1 or MCU also failed to sufficiently increase O2 consumption rates and cytosolic ATP levels in response to high glucose. Glucose-stimulated insulin secretion was reduced by 57.7 and 41.8 % in cells treated with siRNA targeted against MICU1 or MCU, respectively. The presented data illustrate the fundamental role of MICU1 and MCU in the feed-forward mechanism that guarantees sustained insulin secretion and thereby identify the mitochondrial Ca2+ uptake machinery as a promising therapeutic target for type 2 diabetes mellitus.