Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion

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

Summary, in English

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.

Department/s

  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Diabetes - Molecular Metabolism
  • Diabetes - Islet Cell Exocytosis
  • Centre for Analysis and Synthesis

Publishing year

2021-09

Language

English

Publication/Series

Molecular Metabolism

Volume

51

Document type

Journal article

Publisher

Elsevier GmbH

Topic

  • Endocrinology and Diabetes

Keywords

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

Status

Published

Research group

  • LUDC (Lund University Diabetes Centre)
  • Diabetes - Molecular Metabolism
  • Diabetes - Islet Cell Exocytosis

ISBN/ISSN/Other

  • ISSN: 2212-8778