Mitochondrial succinate dehydrogenase is involved in stimulus-secretion coupling and endogenous ROS formation in murine beta cells. 2015

Armin Edalat, and Philipp Schulte-Mecklenbeck, and Cita Bauer, and Sabrina Undank, and Peter Krippeit-Drews, and Gisela Drews, and Martina Düfer
Department of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstraße 48, 48149, Münster, Germany.

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.

UI MeSH Term Description Entries
D007328 Insulin A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1). Iletin,Insulin A Chain,Insulin B Chain,Insulin, Regular,Novolin,Sodium Insulin,Soluble Insulin,Chain, Insulin B,Insulin, Sodium,Insulin, Soluble,Regular Insulin
D007515 Islets of Langerhans Irregular microscopic structures consisting of cords of endocrine cells that are scattered throughout the PANCREAS among the exocrine acini. Each islet is surrounded by connective tissue fibers and penetrated by a network of capillaries. There are four major cell types. The most abundant beta cells (50-80%) secrete INSULIN. Alpha cells (5-20%) secrete GLUCAGON. PP cells (10-35%) secrete PANCREATIC POLYPEPTIDE. Delta cells (~5%) secrete SOMATOSTATIN. Islands of Langerhans,Islet Cells,Nesidioblasts,Pancreas, Endocrine,Pancreatic Islets,Cell, Islet,Cells, Islet,Endocrine Pancreas,Islet Cell,Islet, Pancreatic,Islets, Pancreatic,Langerhans Islands,Langerhans Islets,Nesidioblast,Pancreatic Islet
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D008928 Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed) Mitochondrial Contraction,Mitochondrion,Contraction, Mitochondrial,Contractions, Mitochondrial,Mitochondrial Contractions
D009574 Nitro Compounds Compounds having the nitro group, -NO2, attached to carbon. When attached to nitrogen they are nitramines and attached to oxygen they are NITRATES. Nitrated Compounds
D011422 Propionates Derivatives of propionic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the carboxyethane structure. Propanoate,Propanoic Acid,Propionate,Propanoates,Propanoic Acid Derivatives,Propanoic Acids,Propionic Acid Derivatives,Propionic Acids,Acid, Propanoic,Acids, Propanoic,Acids, Propionic,Derivatives, Propanoic Acid,Derivatives, Propionic Acid
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005182 Flavin-Adenine Dinucleotide A condensation product of riboflavin and adenosine diphosphate. The coenzyme of various aerobic dehydrogenases, e.g., D-amino acid oxidase and L-amino acid oxidase. (Lehninger, Principles of Biochemistry, 1982, p972) FAD,Flavitan,Dinucleotide, Flavin-Adenine,Flavin Adenine Dinucleotide
D005947 Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Dextrose,Anhydrous Dextrose,D-Glucose,Glucose Monohydrate,Glucose, (DL)-Isomer,Glucose, (alpha-D)-Isomer,Glucose, (beta-D)-Isomer,D Glucose,Dextrose, Anhydrous,Monohydrate, Glucose

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