The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic β-cells

Andrei I Tarasov, Francesca Semplici, Magalie A Ravier, Elisa A Bellomo, Timothy J Pullen, Patrick Gilon, Israel Sekler, Rosario Rizzuto, Guy A Rutter

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115 Citations (Scopus)
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Glucose induces insulin release from pancreatic β-cells by stimulating ATP synthesis, membrane depolarisation and Ca(2+) influx. As well as activating ATP-consuming processes, cytosolic Ca(2+) increases may also potentiate mitochondrial ATP synthesis. Until recently, the ability to study the role of mitochondrial Ca(2+) transport in glucose-stimulated insulin secretion has been hindered by the absence of suitable approaches either to suppress Ca(2+) uptake into these organelles, or to examine the impact on β-cell excitability. Here, we have combined patch-clamp electrophysiology with simultaneous real-time imaging of compartmentalised changes in Ca(2+) and ATP/ADP ratio in single primary mouse β-cells, using recombinant targeted (Pericam or Perceval, respectively) as well as entrapped intracellular (Fura-Red), probes. Through shRNA-mediated silencing we show that the recently-identified mitochondrial Ca(2+) uniporter, MCU, is required for depolarisation-induced mitochondrial Ca(2+) increases, and for a sustained increase in cytosolic ATP/ADP ratio. By contrast, silencing of the mitochondrial Na(+)-Ca(2+) exchanger NCLX affected the kinetics of glucose-induced changes in, but not steady state values of, cytosolic ATP/ADP. Exposure to gluco-lipotoxic conditions delayed both mitochondrial Ca(2+) uptake and cytosolic ATP/ADP ratio increases without affecting the expression of either gene. Mitochondrial Ca(2+) accumulation, mediated by MCU and modulated by NCLX, is thus required for normal glucose sensing by pancreatic β-cells, and becomes defective in conditions mimicking the diabetic milieu.

Original languageEnglish
Article numbere39722
Number of pages12
JournalPLoS ONE
Issue number7
Publication statusPublished - 19 Jul 2012


  • Adenosine Triphosphate/metabolism
  • Animals
  • Calcium/metabolism
  • Calcium Channels/genetics
  • Cells, Cultured
  • Female
  • Gene Silencing
  • Glucose/pharmacology
  • Insulin-Secreting Cells/drug effects
  • Mice


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