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. 2001 Jan 15;353(Pt 2):175–180. doi: 10.1042/0264-6021:3530175

Mitochondrial priming modifies Ca2+ oscillations and insulin secretion in pancreatic islets.

E K Ainscow 1, G A Rutter 1
PMCID: PMC1221556  PMID: 11139378

Abstract

Increases in mitochondrial [Ca(2+)] ([Ca(2+)](m)) have recently been reported to cause long-term alterations in cellular ATP production [Jouaville, Bastianutto, Rutter and Rizzuto (1999) Proc. Natl. Acad. Sci. U.S.A. 96, 13807-13812]. We have determined the importance of this phenomenon for nutrient sensing in pancreatic islets and beta-cells by imaging adenovirally expressed Ca(2+) and ATP sensors (aequorin and firefly luciferase). [Ca(2+)](m) increases provoked by KCl or tolbutamide evoked an immediate increase in cytosolic and mitochondrial free ATP concentration ([ATP](c) and [ATP](m) respectively) at 3 mM glucose. Subsequent increases in [glucose] (to 16 or 30 mM) then caused a substantially larger increase in [ATP](c) and [ATP](m) than in naïve cells, and pre-stimulation with tolbutamide led to a larger secretory response in response to glucose. Whereas pre-challenge of islets with KCl altered the response to high [glucose] of [Ca(2+)](m) from periodic oscillations to a sustained elevation, oscillations in [ATP](c) were observed neither in naïve nor in stimulated islets. Hence, long-term potentiation of mitochondrial ATP synthesis is a central element in nutrient recognition by pancreatic islets.

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Selected References

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  1. Ainscow E. K., Zhao C., Rutter G. A. Acute overexpression of lactate dehydrogenase-A perturbs beta-cell mitochondrial metabolism and insulin secretion. Diabetes. 2000 Jul;49(7):1149–1155. doi: 10.2337/diabetes.49.7.1149. [DOI] [PubMed] [Google Scholar]
  2. Bryan J., Aguilar-Bryan L. The ABCs of ATP-sensitive potassium channels: more pieces of the puzzle. Curr Opin Cell Biol. 1997 Aug;9(4):553–559. doi: 10.1016/s0955-0674(97)80033-6. [DOI] [PubMed] [Google Scholar]
  3. Detimary P., Gilon P., Henquin J. C. Interplay between cytoplasmic Ca2+ and the ATP/ADP ratio: a feedback control mechanism in mouse pancreatic islets. Biochem J. 1998 Jul 15;333(Pt 2):269–274. doi: 10.1042/bj3330269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gilon P., Henquin J. C. Influence of membrane potential changes on cytoplasmic Ca2+ concentration in an electrically excitable cell, the insulin-secreting pancreatic B-cell. J Biol Chem. 1992 Oct 15;267(29):20713–20720. [PubMed] [Google Scholar]
  5. Grapengiesser E., Gylfe E., Hellman B. Glucose-induced oscillations of cytoplasmic Ca2+ in the pancreatic beta-cell. Biochem Biophys Res Commun. 1988 Mar 30;151(3):1299–1304. doi: 10.1016/s0006-291x(88)80503-5. [DOI] [PubMed] [Google Scholar]
  6. Grodsky G. M. A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. J Clin Invest. 1972 Aug;51(8):2047–2059. doi: 10.1172/JCI107011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gylfe E. Glucose-induced early changes in cytoplasmic calcium of pancreatic beta-cells studied with time-sharing dual-wavelength fluorometry. J Biol Chem. 1988 Apr 15;263(11):5044–5048. [PubMed] [Google Scholar]
  8. Hajnóczky G., Robb-Gaspers L. D., Seitz M. B., Thomas A. P. Decoding of cytosolic calcium oscillations in the mitochondria. Cell. 1995 Aug 11;82(3):415–424. doi: 10.1016/0092-8674(95)90430-1. [DOI] [PubMed] [Google Scholar]
  9. Halestrap A. P. The regulation of the matrix volume of mammalian mitochondria in vivo and in vitro and its role in the control of mitochondrial metabolism. Biochim Biophys Acta. 1989 Mar 23;973(3):355–382. doi: 10.1016/s0005-2728(89)80378-0. [DOI] [PubMed] [Google Scholar]
  10. He T. C., Zhou S., da Costa L. T., Yu J., Kinzler K. W., Vogelstein B. A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2509–2514. doi: 10.1073/pnas.95.5.2509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jouaville L. S., Pinton P., Bastianutto C., Rutter G. A., Rizzuto R. Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13807–13812. doi: 10.1073/pnas.96.24.13807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jung S. K., Kauri L. M., Qian W. J., Kennedy R. T. Correlated oscillations in glucose consumption, oxygen consumption, and intracellular free Ca(2+) in single islets of Langerhans. J Biol Chem. 2000 Mar 3;275(9):6642–6650. doi: 10.1074/jbc.275.9.6642. [DOI] [PubMed] [Google Scholar]
  13. Kavanagh N. I., Ainscow E. K., Brand M. D. Calcium regulation of oxidative phosphorylation in rat skeletal muscle mitochondria. Biochim Biophys Acta. 2000 Feb 24;1457(1-2):57–70. doi: 10.1016/s0005-2728(00)00054-2. [DOI] [PubMed] [Google Scholar]
  14. Kennedy E. D., Rizzuto R., Theler J. M., Pralong W. F., Bastianutto C., Pozzan T., Wollheim C. B. Glucose-stimulated insulin secretion correlates with changes in mitochondrial and cytosolic Ca2+ in aequorin-expressing INS-1 cells. J Clin Invest. 1996 Dec 1;98(11):2524–2538. doi: 10.1172/JCI119071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kennedy H. J., Pouli A. E., Ainscow E. K., Jouaville L. S., Rizzuto R., Rutter G. A. Glucose generates sub-plasma membrane ATP microdomains in single islet beta-cells. Potential role for strategically located mitochondria. J Biol Chem. 1999 May 7;274(19):13281–13291. doi: 10.1074/jbc.274.19.13281. [DOI] [PubMed] [Google Scholar]
  16. Kennedy H. J., Viollet B., Rafiq I., Kahn A., Rutter G. A. Upstream stimulatory factor-2 (USF2) activity is required for glucose stimulation of L-pyruvate kinase promoter activity in single living islet beta-cells. J Biol Chem. 1997 Aug 15;272(33):20636–20640. doi: 10.1074/jbc.272.33.20636. [DOI] [PubMed] [Google Scholar]
  17. Marchetti P., Scharp D. W., Mclear M., Gingerich R., Finke E., Olack B., Swanson C., Giannarelli R., Navalesi R., Lacy P. E. Pulsatile insulin secretion from isolated human pancreatic islets. Diabetes. 1994 Jun;43(6):827–830. doi: 10.2337/diab.43.6.827. [DOI] [PubMed] [Google Scholar]
  18. McCormack J. G., Halestrap A. P., Denton R. M. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev. 1990 Apr;70(2):391–425. doi: 10.1152/physrev.1990.70.2.391. [DOI] [PubMed] [Google Scholar]
  19. Nakazaki M., Ishihara H., Kakei M., Inukai K., Asano T., Miyazaki J. I., Tanaka H., Kikuchi M., Yada T., Oka Y. Repetitive mitochondrial Ca2+ signals synchronize with cytosolic Ca2+ oscillations in the pancreatic beta-cell line, MIN6. Diabetologia. 1998 Mar;41(3):279–286. doi: 10.1007/s001250050904. [DOI] [PubMed] [Google Scholar]
  20. Nesher R., Cerasi E. Biphasic insulin release as the expression of combined inhibitory and potentiating effects of glucose. Endocrinology. 1987 Sep;121(3):1017–1024. doi: 10.1210/endo-121-3-1017. [DOI] [PubMed] [Google Scholar]
  21. O'Rahilly S., Turner R. C., Matthews D. R. Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med. 1988 May 12;318(19):1225–1230. doi: 10.1056/NEJM198805123181902. [DOI] [PubMed] [Google Scholar]
  22. Patterson G. H., Knobel S. M., Arkhammar P., Thastrup O., Piston D. W. Separation of the glucose-stimulated cytoplasmic and mitochondrial NAD(P)H responses in pancreatic islet beta cells. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5203–5207. doi: 10.1073/pnas.090098797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pouli A. E., Emmanouilidou E., Zhao C., Wasmeier C., Hutton J. C., Rutter G. A. Secretory-granule dynamics visualized in vivo with a phogrin-green fluorescent protein chimaera. Biochem J. 1998 Jul 1;333(Pt 1):193–199. doi: 10.1042/bj3330193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rafiq I., Kennedy H. J., Rutter G. A. Glucose-dependent translocation of insulin promoter factor-1 (IPF-1) between the nuclear periphery and the nucleoplasm of single MIN6 beta-cells. J Biol Chem. 1998 Sep 4;273(36):23241–23247. doi: 10.1074/jbc.273.36.23241. [DOI] [PubMed] [Google Scholar]
  25. Ravier M. A., Gilon P., Henquin J. C. Oscillations of insulin secretion can be triggered by imposed oscillations of cytoplasmic Ca2+ or metabolism in normal mouse islets. Diabetes. 1999 Dec;48(12):2374–2382. doi: 10.2337/diabetes.48.12.2374. [DOI] [PubMed] [Google Scholar]
  26. Rizzuto R., Simpson A. W., Brini M., Pozzan T. Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature. 1992 Jul 23;358(6384):325–327. doi: 10.1038/358325a0. [DOI] [PubMed] [Google Scholar]
  27. Robb-Gaspers L. D., Burnett P., Rutter G. A., Denton R. M., Rizzuto R., Thomas A. P. Integrating cytosolic calcium signals into mitochondrial metabolic responses. EMBO J. 1998 Sep 1;17(17):4987–5000. doi: 10.1093/emboj/17.17.4987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rutter G. A., Burnett P., Rizzuto R., Brini M., Murgia M., Pozzan T., Tavaré J. M., Denton R. M. Subcellular imaging of intramitochondrial Ca2+ with recombinant targeted aequorin: significance for the regulation of pyruvate dehydrogenase activity. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5489–5494. doi: 10.1073/pnas.93.11.5489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rutter G. A. Ca2(+)-binding to citrate cycle dehydrogenases. Int J Biochem. 1990;22(10):1081–1088. doi: 10.1016/0020-711x(90)90105-c. [DOI] [PubMed] [Google Scholar]
  30. Rutter G. A., Theler J. M., Murgia M., Wollheim C. B., Pozzan T., Rizzuto R. Stimulated Ca2+ influx raises mitochondrial free Ca2+ to supramicromolar levels in a pancreatic beta-cell line. Possible role in glucose and agonist-induced insulin secretion. J Biol Chem. 1993 Oct 25;268(30):22385–22390. [PubMed] [Google Scholar]
  31. Schuit F., De Vos A., Farfari S., Moens K., Pipeleers D., Brun T., Prentki M. Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells. J Biol Chem. 1997 Jul 25;272(30):18572–18579. doi: 10.1074/jbc.272.30.18572. [DOI] [PubMed] [Google Scholar]
  32. Seghers V., Nakazaki M., DeMayo F., Aguilar-Bryan L., Bryan J. Sur1 knockout mice. A model for K(ATP) channel-independent regulation of insulin secretion. J Biol Chem. 2000 Mar 31;275(13):9270–9277. doi: 10.1074/jbc.275.13.9270. [DOI] [PubMed] [Google Scholar]
  33. Sekine N., Cirulli V., Regazzi R., Brown L. J., Gine E., Tamarit-Rodriguez J., Girotti M., Marie S., MacDonald M. J., Wollheim C. B. Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic beta-cells. Potential role in nutrient sensing. J Biol Chem. 1994 Feb 18;269(7):4895–4902. [PubMed] [Google Scholar]
  34. Smith P. A., Ashcroft F. M., Rorsman P. Simultaneous recordings of glucose dependent electrical activity and ATP-regulated K(+)-currents in isolated mouse pancreatic beta-cells. FEBS Lett. 1990 Feb 12;261(1):187–190. doi: 10.1016/0014-5793(90)80667-8. [DOI] [PubMed] [Google Scholar]
  35. Zawalich W. S., Zawalich K. C., Rasmussen H. Cholinergic agonists prime the beta-cell to glucose stimulation. Endocrinology. 1989 Nov;125(5):2400–2406. doi: 10.1210/endo-125-5-2400. [DOI] [PubMed] [Google Scholar]

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