Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion

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

Research output: Contribution to journalArticlepeer-review

4 Citations (SciVal)

Abstract

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.

Original languageEnglish
Article number101239
JournalMolecular Metabolism
Volume51
DOIs
Publication statusPublished - 2021 Sep

Bibliographical note

Funding Information:
Laila Jacobsson is acknowledged for genotyping the mice. This study was supported by grants from the Swedish Research Council ( 14196-12-5 and 2017–00956 ), EFSD / MSD , Novo Nordisk Foundation , Swedish Diabetes Foundation , Swedish Strategic Research Foundation , Crafoord , Hjelt , Lars Hierta's Minne , Fredrik och Ingrid Thuring's , O.E. and Edla Johansson's Vetenskapliga , Åke Wibergs , Director, Albert Påhlssons, and Magnus Bergvalls Foundations , and the Royal Physiographic Society . This study was also supported by equipment grants from the KAW Wallenberg Foundation ( 2009–0243 ) and funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement No. 667191 . None of these funding sources were responsible for the study design, collection, analysis, and interpretation of the data or writing the report and decision to submit the article for publication.

Funding Information:
Laila Jacobsson is acknowledged for genotyping the mice. This study was supported by grants from the Swedish Research Council (14196-12-5 and 2017?00956), EFSD/MSD, Novo Nordisk Foundation, Swedish Diabetes Foundation, Swedish Strategic Research Foundation, Crafoord, Hjelt, Lars Hierta's Minne, Fredrik och Ingrid Thuring's, O.E. and Edla Johansson's Vetenskapliga, ?ke Wibergs, Director, Albert P?hlssons, and Magnus Bergvalls Foundations, and the Royal Physiographic Society. This study was also supported by equipment grants from the KAW Wallenberg Foundation (2009?0243) and funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement No. 667191. None of these funding sources were responsible for the study design, collection, analysis, and interpretation of the data or writing the report and decision to submit the article for publication.

Publisher Copyright:
© 2021 The Author(s)

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Subject classification (UKÄ)

  • Endocrinology and Diabetes

Keywords

  • Bioenergetics
  • Knockout mice
  • Mitochondrial calcium uniporter
  • Stimulus-secretion coupling
  • Voltage-dependent calcium channels

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