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Diabetologia
Published in: Diabetologia 7/2015

01-07-2015 | Article

Mitochondrial succinate dehydrogenase is involved in stimulus-secretion coupling and endogenous ROS formation in murine beta cells

Authors: Armin Edalat, Philipp Schulte-Mecklenbeck, Cita Bauer, Sabrina Undank, Peter Krippeit-Drews, Gisela Drews, Martina Düfer

Published in: Diabetologia | Issue 7/2015

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Abstract

Aims/hypothesis

Generation of reduction equivalents is a prerequisite for nutrient-stimulated insulin secretion. Mitochondrial succinate dehydrogenase (SDH) fulfils a dual function with respect to mitochondrial energy supply: (1) the enzyme is part of mitochondrial respiratory chains; and (2) it catalyses oxidation of succinate to fumarate in the Krebs cycle. The aim of our study was to elucidate the significance of SDH for beta cell stimulus-secretion coupling (SSC).

Methods

Mitochondrial variables, reactive oxygen species (ROS) and cytosolic Ca2+ concentration ([Ca2+]c) were measured by fluorescence techniques and insulin release by radioimmunoassay in islets or islet cells of C57Bl/6N mice.

Results

Inhibition of SDH with 3-nitropropionic acid (3-NPA) or monoethyl fumarate (MEF) reduced glucose-stimulated insulin secretion. Inhibition of the ATP-sensitive K+ channel (KATP channel) partly prevented this effect, whereas potentiation of antioxidant defence by superoxide dismutase mimetics (TEMPOL and mito-TEMPO) or by nuclear factor erythroid 2-related factor 2 (Nrf-2)-mediated upregulation of antioxidant enzymes (oltipraz, tert-butylhydroxyquinone) did not diminish the inhibitory influence of 3-NPA. Blocking SDH decreased glucose-stimulated increase in intracellular FADH2 concentration without alterations in NAD(P)H. In addition, 3-NPA and MEF drastically reduced glucose-induced hyperpolarisation of mitochondrial membrane potential, indicative of decreased ATP production. As a consequence, the glucose-stimulated rise in [Ca2+]c was significantly delayed and reduced. Acute application of 3-NPA interrupted glucose-driven oscillations of [Ca2+]c. 3-NPA per se did not elevate intracellular ROS, but instead prevented glucose-induced ROS accumulation.

Conclusions/interpretation

SDH is an important regulator of insulin secretion and ROS production. Inhibition of SDH interrupts membrane-potential-dependent SSC, pointing to a pivotal role of mitochondrial FAD/FADH2 homeostasis for the maintenance of glycaemic control.
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Metadata
Title
Mitochondrial succinate dehydrogenase is involved in stimulus-secretion coupling and endogenous ROS formation in murine beta cells
Authors
Armin Edalat
Philipp Schulte-Mecklenbeck
Cita Bauer
Sabrina Undank
Peter Krippeit-Drews
Gisela Drews
Martina Düfer
Publication date
01-07-2015
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 7/2015
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-015-3577-9

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