Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion
Objective: Transport of Ca2+ into pancreatic β cell mitochondria facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. Recent establishment of the molecular identity of the mitochondrial Ca2+ uniporter (MCU) and associated proteins allows modification of mito...
Main Authors: | , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2021-09-01
|
Series: | Molecular Metabolism |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877821000843 |
id |
doaj-2eb31893a8d9416abeb1dba8affc20f2 |
---|---|
record_format |
Article |
spelling |
doaj-2eb31893a8d9416abeb1dba8affc20f22021-08-20T04:34:48ZengElsevierMolecular Metabolism2212-87782021-09-0151101239Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretionN. Vishnu0A. Hamilton1A. Bagge2A. Wernersson3E. Cowan4H. Barnard5Y. Sancak6K.J. Kamer7P. Spégel8M. Fex9A. Tengholm10V.K. Mootha11D.G. Nicholls12H. Mulder13Unit of Molecular Metabolism, Lund University Diabetes Center, Lund University, Malmö SE-205 02, SwedenUnit of Molecular Metabolism, Lund University Diabetes Center, Lund University, Malmö SE-205 02, SwedenUnit of Molecular Metabolism, Lund University Diabetes Center, Lund University, Malmö SE-205 02, SwedenUnit of Molecular Metabolism, Lund University Diabetes Center, Lund University, Malmö SE-205 02, SwedenUnit of Molecular Metabolism, Lund University Diabetes Center, Lund University, Malmö SE-205 02, SwedenUnit of Molecular Metabolism, Lund University Diabetes Center, Lund University, Malmö SE-205 02, SwedenBroad Institute of Harvard and MIT, Cambridge, MA 02142, USABroad Institute of Harvard and MIT, Cambridge, MA 02142, USAUnit of Molecular Metabolism, Lund University Diabetes Center, Lund University, Malmö SE-205 02, SwedenUnit of Molecular Metabolism, Lund University Diabetes Center, Lund University, Malmö SE-205 02, SwedenDepartment of Medical Cell Biology, Uppsala University, Uppsala SE-751 23, SwedenBroad Institute of Harvard and MIT, Cambridge, MA 02142, USAUnit of Molecular Metabolism, Lund University Diabetes Center, Lund University, Malmö SE-205 02, Sweden; Buck Institute for Research on Aging, Novato, CA 94945, USAUnit of Molecular Metabolism, Lund University Diabetes Center, Lund University, Malmö SE-205 02, Sweden; Corresponding author.Objective: Transport of Ca2+ into pancreatic β cell mitochondria facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. Recent establishment of the molecular identity of the mitochondrial Ca2+ uniporter (MCU) and associated proteins allows modification of mitochondrial Ca2+ 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-βH1 cell lines was performed; Micu2−/− mice were also studied. Insulin secretion and mechanistic analyses utilizing live confocal imaging to assess mitochondrial function and intracellular Ca2+ dynamics were performed. Results: Silencing of Micu2 abrogated GSIS in the INS-1 832/13 and EndoC-βH1 cells. The Micu2−/− mice also displayed attenuated GSIS. Mitochondrial Ca2+ uptake declined in MICU2-deficient INS-1 832/13 and EndoC-βH1 cells in response to high glucose and high K+. MICU2 silencing in INS-1 832/13 cells, presumably through its effects on mitochondrial Ca2+ 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 Ca2+ uptake, cytosolic Ca2+ was lower in siMICU2-treated INS-1 832/13 cells in response to high K+. It was hypothesized that Ca2+ accumulated in the submembrane compartment in MICU2-deficient cells, resulting in desensitization of voltage-dependent Ca2+ channels, lowering total cytosolic Ca2+. Upon high K+ stimulation, MICU2-silenced cells showed higher and prolonged increases in submembrane Ca2+ levels. Conclusions: MICU2 plays a critical role in β cell mitochondrial Ca2+ uptake. β cell mitochondria sequestered Ca2+ from the submembrane compartment, preventing desensitization of voltage-dependent Ca2+ channels and facilitating GSIS.http://www.sciencedirect.com/science/article/pii/S2212877821000843Mitochondrial calcium uniporterVoltage-dependent calcium channelsBioenergeticsKnockout miceStimulus-secretion coupling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
N. Vishnu A. Hamilton A. Bagge A. Wernersson E. Cowan H. Barnard Y. Sancak K.J. Kamer P. Spégel M. Fex A. Tengholm V.K. Mootha D.G. Nicholls H. Mulder |
spellingShingle |
N. Vishnu A. Hamilton A. Bagge A. Wernersson E. Cowan H. Barnard Y. Sancak K.J. Kamer P. Spégel M. Fex A. Tengholm V.K. Mootha D.G. Nicholls H. Mulder Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion Molecular Metabolism Mitochondrial calcium uniporter Voltage-dependent calcium channels Bioenergetics Knockout mice Stimulus-secretion coupling |
author_facet |
N. Vishnu A. Hamilton A. Bagge A. Wernersson E. Cowan H. Barnard Y. Sancak K.J. Kamer P. Spégel M. Fex A. Tengholm V.K. Mootha D.G. Nicholls H. Mulder |
author_sort |
N. Vishnu |
title |
Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion |
title_short |
Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion |
title_full |
Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion |
title_fullStr |
Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion |
title_full_unstemmed |
Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion |
title_sort |
mitochondrial clearance of calcium facilitated by micu2 controls insulin secretion |
publisher |
Elsevier |
series |
Molecular Metabolism |
issn |
2212-8778 |
publishDate |
2021-09-01 |
description |
Objective: Transport of Ca2+ into pancreatic β cell mitochondria facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. Recent establishment of the molecular identity of the mitochondrial Ca2+ uniporter (MCU) and associated proteins allows modification of mitochondrial Ca2+ 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-βH1 cell lines was performed; Micu2−/− mice were also studied. Insulin secretion and mechanistic analyses utilizing live confocal imaging to assess mitochondrial function and intracellular Ca2+ dynamics were performed. Results: Silencing of Micu2 abrogated GSIS in the INS-1 832/13 and EndoC-βH1 cells. The Micu2−/− mice also displayed attenuated GSIS. Mitochondrial Ca2+ uptake declined in MICU2-deficient INS-1 832/13 and EndoC-βH1 cells in response to high glucose and high K+. MICU2 silencing in INS-1 832/13 cells, presumably through its effects on mitochondrial Ca2+ 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 Ca2+ uptake, cytosolic Ca2+ was lower in siMICU2-treated INS-1 832/13 cells in response to high K+. It was hypothesized that Ca2+ accumulated in the submembrane compartment in MICU2-deficient cells, resulting in desensitization of voltage-dependent Ca2+ channels, lowering total cytosolic Ca2+. Upon high K+ stimulation, MICU2-silenced cells showed higher and prolonged increases in submembrane Ca2+ levels. Conclusions: MICU2 plays a critical role in β cell mitochondrial Ca2+ uptake. β cell mitochondria sequestered Ca2+ from the submembrane compartment, preventing desensitization of voltage-dependent Ca2+ channels and facilitating GSIS. |
topic |
Mitochondrial calcium uniporter Voltage-dependent calcium channels Bioenergetics Knockout mice Stimulus-secretion coupling |
url |
http://www.sciencedirect.com/science/article/pii/S2212877821000843 |
work_keys_str_mv |
AT nvishnu mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT ahamilton mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT abagge mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT awernersson mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT ecowan mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT hbarnard mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT ysancak mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT kjkamer mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT pspegel mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT mfex mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT atengholm mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT vkmootha mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT dgnicholls mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion AT hmulder mitochondrialclearanceofcalciumfacilitatedbymicu2controlsinsulinsecretion |
_version_ |
1721201656363745280 |