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

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Tarasov, Andrei I Semplici, Francesca Ravier, Magalie A Bellomo, Elisa A Pullen, Timothy J Gilon, Patrick [UCL] Rutter, Guy A

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.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2012
Language Anglais
Journal information "PLoS One" - Vol. 7, no.7, p. e39722 [1-12] (2012)
Peer reviewed yes
Publisher Public Library of Science ((United States) San Francisco, CA)
issn 1932-6203
Publication status Publié
Affiliation UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition
MESH Subject Adenosine Triphosphate ; Mice ; Animals ; Calcium ; Calcium Channels ; Cells, Cultured ; Female ; Gene Silencing ; Glucose ; Insulin-Secreting Cells
Links
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Bibliographic reference Tarasov, Andrei I ; Semplici, Francesca ; Ravier, Magalie A ; Bellomo, Elisa A ; Pullen, Timothy J ; et. al. The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic β-cells.. In: PLoS One, Vol. 7, no.7, p. e39722 [1-12] (2012)
Permanent URL http://hdl.handle.net/2078.1/131893