title: Mitochondrial succinate dehydrogenase is involved in stimulus-secretion coupling and endogenous ROS formation in murine beta cells.
abstract: OBJECTIVE
  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 Ca(2+) concentration ([Ca(2+)]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 [Ca(2+)]c was significantly delayed and reduced. Acute application of 3-NPA interrupted glucose-driven oscillations of [Ca(2+)]c. 3-NPA per se did not elevate intracellular ROS, but instead prevented glucose-induced ROS accumulation.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstraße 48, 48149, Münster, Germany.
authors: Armin
authors: A
authors: Edalat
authors: Philipp
authors: P
authors: Schulte-Mecklenbeck
authors: Cita
authors: C
authors: Bauer
authors: Sabrina
authors: S
authors: Undank
authors: Peter
authors: P
authors: Krippeit-Drews
authors: Gisela
authors: G
authors: Drews
authors: Martina
authors: M
authors: Düfer
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology*; D009574:Nitro Compounds / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D054086:KATP Channels; D009574:Nitro Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D013453:Sulfonylurea Compounds; D005182:Flavin-Adenine Dinucleotide; D013385:Succinate Dehydrogenase; D005947:Glucose; C015392:3-nitropropionic acid; D002118:Calcium