Uncoupling protein-2 contributes significantly to high mitochondrial proton leak in INS-1E insulinoma cells and attenuates glucose-stimulated insulin secretion.

TitleUncoupling protein-2 contributes significantly to high mitochondrial proton leak in INS-1E insulinoma cells and attenuates glucose-stimulated insulin secretion.
Publication TypeJournal Article
Year of Publication2008
AuthorsAffourtit, C, Brand, MD
JournalBiochem J
Volume409
Issue1
Pagination199-204
Date Published2008 Jan 01
ISSN1470-8728
KeywordsAnimals, Cytoplasm, Glucose, Insulin, Insulin Secretion, Insulin-Secreting Cells, Ion Channels, Membrane Potentials, Methacrylates, Mitochondria, Mitochondrial Proteins, Oligomycins, Oxygen, Oxygen Consumption, Phosphorylation, Rats, RNA Interference, Thiazoles, Uncoupling Protein 2
Abstract

Proton leak exerts stronger control over ATP/ADP in mitochondria from clonal pancreatic beta-cells (INS-1E) than in those from rat skeletal muscle, due to the higher proton conductance of INS-1E mitochondria [Affourtit and Brand (2006) Biochem. J. 393, 151-159]. In the present study, we demonstrate that high proton leak manifests itself at the cellular level too: the leak rate (measured as myxothiazol-sensitive, oligomycin-resistant respiration) was nearly four times higher in INS-1E cells than in myoblasts. This relatively high leak activity was decreased more than 30% upon knock-down of UCP2 (uncoupling protein-2) by RNAi (RNA interference). The high contribution of UCP2 to leak suggests that proton conductance through UCP2 accounts for approx. 20% of INS-1E respiration. UCP2 knock-down enhanced GSIS (glucose-stimulated insulin secretion), consistent with a role for UCP2 in beta-cell physiology. We propose that the high mitochondrial proton leak in beta-cells is a mechanism which amplifies the effect of physiological UCP2 regulators on cytoplasmic ATP/ADP and hence on insulin secretion.

DOI10.1042/BJ20070954
Alternate JournalBiochem. J.
Citation Key10.1042/BJ20070954
PubMed ID17824844
Grant ListMC_U105663137 / / Medical Research Council / United Kingdom