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

Title: The mitochondrial Ca2+ uniporter MCU Is essential for glucose-induced ATP increases in pancreatic beta-cells
Authors: Tarasov, AI
Semplici, F
Ravier, MA
Bellomo, EA
Pullen, TJ
Gilon, P
Sekler, I
Rizzuto, R
Rutter, GA
Item Type: Journal Article
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.
Issue Date: 19-Jul-2012
Date of Acceptance: 25-May-2012
URI: http://hdl.handle.net/10044/1/43720
DOI: http://dx.doi.org/10.1371/journal.pone.0039722
ISSN: 1932-6203
Publisher: Public Library of Science
Journal / Book Title: PLOS One
Volume: 7
Issue: 7
Copyright Statement: © 2012 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Medical Research Council (MRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
Funder's Grant Number: G0401641
BB/J015873/1
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MULTIDISCIPLINARY SCIENCES
INDUCED INSULIN-SECRETION
SENSITIVE K+ CHANNEL
ESSENTIAL COMPONENT
CALCIUM UNIPORTER
CYTOPLASMIC CA2+
CYTOSOLIC CA2+
FATTY-ACIDS
B-CELL
ISLETS
OSCILLATIONS
Adenosine Triphosphate
Animals
Calcium
Calcium Channels
Cells, Cultured
Female
Gene Silencing
Glucose
Insulin-Secreting Cells
Mice
General Science & Technology
MD Multidisciplinary
Publication Status: Published
Article Number: ARTN e39722
Appears in Collections:Department of Medicine
Faculty of Medicine



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