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Differential effect of glucose on ER-mitochondria Ca(2+) exchange participates to insulin secretion and to glucotoxicity-mediated dysfunction of beta cells
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Edité par CCSD ; American Diabetes Association -
International audience. Glucotoxicity-induced beta cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and endoplasmic reticulum (ER). Both organelles interact at contact sites, defined as mitochondria-associated membranes (MAMs), which were recently implicated in the regulation of glucose homeostasis. The role of MAMs in beta cells is still largely unknown and their implication in glucotoxicity-associated beta cell dysfunction remains to be defined. Here, we report that acute glucose stimulation stimulated ER-mitochondria interactions and calcium (Ca(2+)) exchange in INS-1E cells, whereas disruption of MAMs altered glucose-stimulated insulin secretion (GSIS). Conversely, chronic incubations with high glucose of either INS-1E cells or human pancreatic islets altered GSIS, and concomitantly reduced ER Ca(2+) store, increased basal mitochondrial Ca(2+) and reduced ATP-stimulated ER-mitochondria Ca(2+) exchanges, despite an increase of organelle interactions. Furthermore, glucotoxicity-induced perturbations of Ca(2+) signaling are associated with ER stress, altered mitochondrial respiration and mitochondria fragmentation, and these organelle stresses may participate to increased organelle tethering, as a protective mechanism. Lastly, sustained induction of ER-mitochondria interactions using a linker reduced organelle Ca(2+) exchange, induced mitochondrial fission and altered GSIS. Therefore, dynamic organelle coupling participates to GSIS in beta cells and over-time disruption of organelle Ca(2+) exchange might be a novel mechanism contributing to glucotoxicity-induced beta cell dysfunction.
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