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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Abstract

Glucose induces insulin release from pancreatic β-cells by stimulating ATP synthesis, membrane depolarisation and Ca2+ influx. As well as activating ATP-consuming processes, cytosolic Ca2+ increases may also potentiate mitochondrial ATP synthesis. Until recently, the ability to study the role of mitochondrial Ca2+ transport in glucose-stimulated insulin secretion has been hindered by the absence of suitable approaches either to suppress Ca2+ 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 Ca2+ 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 Ca2+ uniporter, MCU, is required for depolarisation-induced mitochondrial Ca2+ increases, and for a sustained increase in cytosolic ATP/ADP ratio. By contrast, silencing of the mitochondrial Na+-Ca2+ 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 Ca2+ uptake and cytosolic ATP/ADP ratio increases without affecting the expression of either gene. Mitochondrial Ca2+ 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
JournalPLoS ONE
Volume7
Issue number7
DOIs
Publication statusPublished - 19 Jul 2012

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    Tarasov, A. I., Semplici, F., Ravier, M. A., Bellomo, E. A., Pullen, T. J., Gilon, P., Sekler, I., Rizzuto, R., & Rutter, G. A. (2012). The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced atp increases in pancreatic β-cells. PLoS ONE, 7(7), [e39722]. https://doi.org/10.1371/journal.pone.0039722