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David Nicholls

Visiting research fellow

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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

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.


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

Publishing year





Molecular Metabolism



Document type

Journal article




  • Endocrinology and Diabetes


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



Research group

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


  • ISSN: 2212-8778