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Alam, MR; Groschner, LN; Parichatikanond, W; Kuo, L; Bondarenko, AI; Rost, R; Waldeck-Weiermair, M; Malli, R; Graier, WF.
Mitochondrial Ca2+ uptake 1 (MICU1) and mitochondrial ca2+ uniporter (MCU) contribute to metabolism-secretion coupling in clonal pancreatic β-cells.
J Biol Chem. 2012; 287(41):34445-34454 Doi: 10.1074/jbc.M112.392084 [OPEN ACCESS]
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Leading authors Med Uni Graz: Alam Muhammad Rizwan; Graier Wolfgang
Co-authors Med Uni Graz: Bondarenko Oleksandr; Groschner Lukas; Malli Roland; Parichatikanond Warisara; Rost René; Waldeck-Weiermair Markus
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Abstract:: In pancreatic β-cells, uptake of Ca(2+) into mitochondria facilitates metabolism-secretion coupling by activation of various matrix enzymes, thus facilitating ATP generation by oxidative phosphorylation and, in turn, augmenting insulin release. We employed an siRNA-based approach to evaluate the individual contribution of four proteins that were recently described to be engaged in mitochondrial Ca(2+) sequestration in clonal INS-1 832/13 pancreatic β-cells: the mitochondrial Ca(2+) uptake 1 (MICU1), mitochondrial Ca(2+) uniporter (MCU), uncoupling protein 2 (UCP2), and leucine zipper EF-hand-containing transmembrane protein 1 (LETM1). Using a FRET-based genetically encoded Ca(2+) sensor targeted to mitochondria, we show that a transient knockdown of MICU1 or MCU diminished mitochondrial Ca(2+) uptake upon both intracellular Ca(2+) release and Ca(2+) entry via L-type channels. In contrast, knockdown of UCP2 and LETM1 exclusively reduced mitochondrial Ca(2+) uptake in response to either intracellular Ca(2+) release or Ca(2+) entry, respectively. Therefore, we further investigated the role of MICU1 and MCU in metabolism-secretion coupling. Diminution of MICU1 or MCU reduced mitochondrial Ca(2+) uptake in response to d-glucose, whereas d-glucose-triggered cytosolic Ca(2+) oscillations remained unaffected. Moreover, d-glucose-evoked increases in cytosolic ATP and d-glucose-stimulated insulin secretion were diminished in MICU1- or MCU-silenced cells. Our data highlight the crucial role of MICU1 and MCU in mitochondrial Ca(2+) uptake in pancreatic β-cells and their involvement in the positive feedback required for sustained insulin secretion.
Find related publications in this database (using NLM MeSH Indexing): Adenosine Triphosphate - genetics Adenosine Triphosphate - metabolism; Calcium - metabolism; Calcium Channels - genetics Calcium Channels - metabolism; Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism; Cation Transport Proteins - genetics Cation Transport Proteins - metabolism; Cell Line -; Endopeptidases - genetics Endopeptidases - metabolism; Gene Knockdown Techniques -; Glucose - genetics Glucose - metabolism; Humans -; Insulin - genetics Insulin - secretion; Insulin-Secreting Cells - cytology Insulin-Secreting Cells - secretion; Membrane Proteins - genetics Membrane Proteins - metabolism; Mitochondrial Membrane Transport Proteins - genetics Mitochondrial Membrane Transport Proteins - metabolism