Review
Mitochondrial signals drive insulin secretion in the pancreatic b-cell
Andreas Wiederkehr
a,
⇑
, Claes B. Wollheim
b,
⇑
a
Nestlé Institute of Health Sciences, 1015 Lausanne, Switzerland
b
Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland
article info
Article history:
Available online 19 July 2011
This article is dedicated to Prof. Andras Spät
at the occasion of his 70th birthday.
Keywords:
b-Cell
Islet
Metabolism–secretion coupling
Calcium
Mitochondrial matrix pH
S100G
abstract
b-Cell nutrient sensing depends on mitochondrial function. Oxidation of nutrient-derived metabolites in
the mitochondria leads to plasma membrane depolarization, Ca
2+
influx and insulin granule exocytosis.
Subsequent mitochondrial Ca
2+
uptake further accelerates metabolism and oxidative phosphorylation.
Nutrient activation also increases the mitochondrial matrix pH. This alkalinization is required to maintain
elevated insulin secretion during prolonged nutrient stimulation. Together the mitochondrial Ca
2+
rise
and matrix alkalinization assure optimal ATP synthesis necessary for efficient activation of the triggering
pathway of insulin secretion. The sustained, amplifying pathway of insulin release also depends on mito-
chondrial Ca
2+
signals, which likely influence the generation of glucose-derived metabolites serving as
coupling factors. Therefore, mitochondria are both recipients and generators of signals essential for
metabolism-secretion coupling. Activation of these signaling pathways would be an attractive target
for the improvement of b-cell function and the treatment of type 2 diabetes.
Ó 2011 Elsevier Ireland Ltd. All rights reserved.
Contents
1. Introduction ......................................................................................................... 129
2. b-Cell nutrient sensing. . . . . . . . ......................................................................................... 130
3. Metabolism of nutrient secretagogues . . . . . . . . . . . . . . ...................................................................... 130
4. Nutrient oxidation . . . . . . . . . . . ......................................................................................... 130
5. Mitochondrial respiration in metabolism-secretion coupling . . . . . . . . . . . . . . . ................................................... 131
6. Hyperpolarization of the mitochondrial membrane potential and ATP synthesis in insulin secreting cells . . . . . . . . . . . . . ................ 131
7. Anaplerosis and the generation of coupling factors . . . . ...................................................................... 132
8. NADPH as a coupling factor. . . . ......................................................................................... 132
9. Signaling role for mitochondrial GTP . . . . . . . . . . . . . . . ...................................................................... 133
10. Glutamate, glutamine and
a
-ketoglutarate: key metabolites . . . . . . . . . . . . . . . ................................................... 133
11. Mitochondrial Ca
2+
a signal for glucose-stimulated insulin secretion. . . . . . . . . ................................................... 133
12. Ca
2+
-regulated mitochondrial proteins . . . . . . . . . . . . . . ...................................................................... 134
13. Ca
2+
signals activate energy metabolism . . . . . . . . . . . . ...................................................................... 134
14. Signaling role of matrix Ca
2+
in situ ...................................................................................... 134
15. Enhanced matrix Ca
2+
signaling restores impaired insulin secretion . . . . . . . . . ................................................... 134
16. Mitochondrial matrix pH a novel regulator of b-cell energy metabolism . . . . . ................................................... 134
17. Conclusion . ......................................................................................................... 135
Acknowledgements . . . . . . . . . . ......................................................................................... 135
References . ......................................................................................................... 135
0303-7207/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.mce.2011.07.016
Abbreviations: AGC, aspartate–glutamate carrier; BCATm, branched chain amino transferase; cICD, cytosolic isocitrate dehydrogenase; GDH, glutamate dehydrogenase;
GLP-1, glucagon-like peptide-1; LDH, lactate dehydrogenase; mtDNA, mitochondrial DNA; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PEP, phosphoenolpyr-
uvate; SCS, succinyl-CoA synthetase; Tfam, mitochondrial transcription factor A; TFB1M, mitochondrial transcription factor B1.
⇑
Corresponding authors. Address: Department of Cell Physiology and Metabolism, University Medical Center, 1, rue Michel-Servet, 1211 Geneva 4, Switzerland. Tel.: +41
22 379 55 48; fax: +41 22 379 52 60.
E-mail addresses: andreas.wiederkehr@nestle.com, andreas.wiederkehr@unige.ch (A. Wiederkehr), claes.wollheim@unige.ch (C.B. Wollheim).
Molecular and Cellular Endocrinology 353 (2012) 128–137
Contents lists available at ScienceDirect
Molecular and Cellular Endocrinology
journal homepage: www.elsevier.com/locate/mce