| First Author | Vishnu N | Year | 2021 |
| Journal | Mol Metab | Volume | 51 |
| Pages | 101239 | PubMed ID | 33932586 |
| Mgi Jnum | J:325143 | Mgi Id | MGI:6714634 |
| Doi | 10.1016/j.molmet.2021.101239 | Citation | Vishnu N, et al. (2021) Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion. Mol Metab 51:101239 |
| abstractText | OBJECTIVE: Transport of Ca(2+) into pancreatic beta cell mitochondria facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. Recent establishment of the molecular identity of the mitochondrial Ca(2+) uniporter (MCU) and associated proteins allows modification of mitochondrial Ca(2+) transport in intact cells. We examined the consequences of deficiency of the accessory protein MICU2 in rat and human insulin-secreting cells and mouse islets. METHODS: siRNA silencing of Micu2 in the INS-1 832/13 and EndoC-betaH1 cell lines was performed; Micu2(-/-) mice were also studied. Insulin secretion and mechanistic analyses utilizing live confocal imaging to assess mitochondrial function and intracellular Ca(2+) dynamics were performed. RESULTS: Silencing of Micu2 abrogated GSIS in the INS-1 832/13 and EndoC-betaH1 cells. The Micu2(-/-) mice also displayed attenuated GSIS. Mitochondrial Ca(2+) uptake declined in MICU2-deficient INS-1 832/13 and EndoC-betaH1 cells in response to high glucose and high K(+). MICU2 silencing in INS-1 832/13 cells, presumably through its effects on mitochondrial Ca(2+) uptake, perturbed mitochondrial function illustrated by absent mitochondrial membrane hyperpolarization and lowering of the ATP/ADP ratio in response to elevated glucose. Despite the loss of mitochondrial Ca(2+) uptake, cytosolic Ca(2+) was lower in siMICU2-treated INS-1 832/13 cells in response to high K(+). It was hypothesized that Ca(2+) accumulated in the submembrane compartment in MICU2-deficient cells, resulting in desensitization of voltage-dependent Ca(2+) channels, lowering total cytosolic Ca(2+). Upon high K(+) stimulation, MICU2-silenced cells showed higher and prolonged increases in submembrane Ca(2+) levels. CONCLUSIONS: MICU2 plays a critical role in beta cell mitochondrial Ca(2+) uptake. beta cell mitochondria sequestered Ca(2+) from the submembrane compartment, preventing desensitization of voltage-dependent Ca(2+) channels and facilitating GSIS. |
