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. 1999 Jul;77(1):37–44. doi: 10.1016/S0006-3495(99)76870-0

Impact of mitochondrial Ca2+ cycling on pattern formation and stability.

M Falcke 1, J L Hudson 1, P Camacho 1, J D Lechleiter 1
PMCID: PMC1300310  PMID: 10388738

Abstract

Energization of mitochondria significantly alters the pattern of Ca2+ wave activity mediated by activation of the inositol (1,4,5) trisphosphate (IP3) receptor (IP3R) in Xenopus oocytes. The number of pulsatile foci is reduced and spiral Ca2+ waves are no longer observed. Rather, target patterns of Ca2+ release predominate, and when fragmented, fail to form spirals. Ca2+ wave velocity, amplitude, decay time, and periodicity are also increased. We have simulated these experimental findings by supplementing an existing mathematical model with a differential equation for mitochondrial Ca2+ uptake and release. Our calculations show that mitochondrial Ca2+ efflux plays a critical role in pattern formation by prolonging the recovery time of IP3Rs from a refractory state. We also show that under conditions of high energization of mitochondria, the Ca2+ dynamics can become bistable with a second stable stationary state of high resting Ca2+ concentration.

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Selected References

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  1. Allbritton N. L., Meyer T., Stryer L. Range of messenger action of calcium ion and inositol 1,4,5-trisphosphate. Science. 1992 Dec 11;258(5089):1812–1815. doi: 10.1126/science.1465619. [DOI] [PubMed] [Google Scholar]
  2. Amundson J., Clapham D. Calcium waves. Curr Opin Neurobiol. 1993 Jun;3(3):375–382. doi: 10.1016/0959-4388(93)90131-h. [DOI] [PubMed] [Google Scholar]
  3. Atri A., Amundson J., Clapham D., Sneyd J. A single-pool model for intracellular calcium oscillations and waves in the Xenopus laevis oocyte. Biophys J. 1993 Oct;65(4):1727–1739. doi: 10.1016/S0006-3495(93)81191-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berridge M. J. Inositol trisphosphate and calcium signalling. Nature. 1993 Jan 28;361(6410):315–325. doi: 10.1038/361315a0. [DOI] [PubMed] [Google Scholar]
  5. Bezprozvanny I., Watras J., Ehrlich B. E. Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature. 1991 Jun 27;351(6329):751–754. doi: 10.1038/351751a0. [DOI] [PubMed] [Google Scholar]
  6. Blatter L. A., Wier W. G. Agonist-induced [Ca2+]i waves and Ca(2+)-induced Ca2+ release in mammalian vascular smooth muscle cells. Am J Physiol. 1992 Aug;263(2 Pt 2):H576–H586. doi: 10.1152/ajpheart.1992.263.2.H576. [DOI] [PubMed] [Google Scholar]
  7. Bygrave F. L., Reed K. C., Spencer T. Cooperative interactions in energy-dependent accumulation of Ca2+ by isolated rat liver mitochondria. Nat New Biol. 1971 Mar 17;230(11):89–89. doi: 10.1038/newbio230089a0. [DOI] [PubMed] [Google Scholar]
  8. Camacho P., Lechleiter J. D. Increased frequency of calcium waves in Xenopus laevis oocytes that express a calcium-ATPase. Science. 1993 Apr 9;260(5105):226–229. doi: 10.1126/science.8385800. [DOI] [PubMed] [Google Scholar]
  9. Camacho P., Lechleiter J. D. Spiral calcium waves: implications for signalling. Ciba Found Symp. 1995;188:66–84. doi: 10.1002/9780470514696.ch5. [DOI] [PubMed] [Google Scholar]
  10. Clapham D. E. Calcium signaling. Cell. 1995 Jan 27;80(2):259–268. doi: 10.1016/0092-8674(95)90408-5. [DOI] [PubMed] [Google Scholar]
  11. Cornell-Bell A. H., Finkbeiner S. M., Cooper M. S., Smith S. J. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science. 1990 Jan 26;247(4941):470–473. doi: 10.1126/science.1967852. [DOI] [PubMed] [Google Scholar]
  12. Davidenko J. M., Pertsov A. V., Salomonsz R., Baxter W., Jalife J. Stationary and drifting spiral waves of excitation in isolated cardiac muscle. Nature. 1992 Jan 23;355(6358):349–351. doi: 10.1038/355349a0. [DOI] [PubMed] [Google Scholar]
  13. De Young G. W., Keizer J. A single-pool inositol 1,4,5-trisphosphate-receptor-based model for agonist-stimulated oscillations in Ca2+ concentration. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9895–9899. doi: 10.1073/pnas.89.20.9895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. DeLisle S., Welsh M. J. Inositol trisphosphate is required for the propagation of calcium waves in Xenopus oocytes. J Biol Chem. 1992 Apr 25;267(12):7963–7966. [PubMed] [Google Scholar]
  15. Devreotes P. N., Potel M. J., MacKay S. A. Quantitative analysis of cyclic AMP waves mediating aggregation in Dictyostelium discoideum. Dev Biol. 1983 Apr;96(2):405–415. doi: 10.1016/0012-1606(83)90178-1. [DOI] [PubMed] [Google Scholar]
  16. Dolmetsch R. E., Xu K., Lewis R. S. Calcium oscillations increase the efficiency and specificity of gene expression. Nature. 1998 Apr 30;392(6679):933–936. doi: 10.1038/31960. [DOI] [PubMed] [Google Scholar]
  17. Dupont G., Berridge M. J., Goldbeter A. Signal-induced Ca2+ oscillations: properties of a model based on Ca(2+)-induced Ca2+ release. Cell Calcium. 1991 Feb-Mar;12(2-3):73–85. doi: 10.1016/0143-4160(91)90010-c. [DOI] [PubMed] [Google Scholar]
  18. Eidne K. A., Zabavnik J., Allan W. T., Trewavas A. J., Read N. D., Anderson L. Calcium waves and dynamics visualized by confocal microscopy in Xenopus oocytes expressing cloned TRH receptors. J Neuroendocrinol. 1994 Apr;6(2):173–178. doi: 10.1111/j.1365-2826.1994.tb00569.x. [DOI] [PubMed] [Google Scholar]
  19. Fewtrell C. Ca2+ oscillations in non-excitable cells. Annu Rev Physiol. 1993;55:427–454. doi: 10.1146/annurev.ph.55.030193.002235. [DOI] [PubMed] [Google Scholar]
  20. Finch E. A., Turner T. J., Goldin S. M. Calcium as a coagonist of inositol 1,4,5-trisphosphate-induced calcium release. Science. 1991 Apr 19;252(5004):443–446. doi: 10.1126/science.2017683. [DOI] [PubMed] [Google Scholar]
  21. Fontanilla R. A., Nuccitelli R. Characterization of the sperm-induced calcium wave in Xenopus eggs using confocal microscopy. Biophys J. 1998 Oct;75(4):2079–2087. doi: 10.1016/S0006-3495(98)77650-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gorelova N. A., Bures J. Spiral waves of spreading depression in the isolated chicken retina. J Neurobiol. 1983 Sep;14(5):353–363. doi: 10.1002/neu.480140503. [DOI] [PubMed] [Google Scholar]
  23. Gu X., Spitzer N. C. Distinct aspects of neuronal differentiation encoded by frequency of spontaneous Ca2+ transients. Nature. 1995 Jun 29;375(6534):784–787. doi: 10.1038/375784a0. [DOI] [PubMed] [Google Scholar]
  24. Gunter T. E., Pfeiffer D. R. Mechanisms by which mitochondria transport calcium. Am J Physiol. 1990 May;258(5 Pt 1):C755–C786. doi: 10.1152/ajpcell.1990.258.5.C755. [DOI] [PubMed] [Google Scholar]
  25. Harris-White M. E., Zanotti S. A., Frautschy S. A., Charles A. C. Spiral intercellular calcium waves in hippocampal slice cultures. J Neurophysiol. 1998 Feb;79(2):1045–1052. doi: 10.1152/jn.1998.79.2.1045. [DOI] [PubMed] [Google Scholar]
  26. Hehl S., Golard A., Hille B. Involvement of mitochondria in intracellular calcium sequestration by rat gonadotropes. Cell Calcium. 1996 Dec;20(6):515–524. doi: 10.1016/s0143-4160(96)90094-9. [DOI] [PubMed] [Google Scholar]
  27. Herrington J., Park Y. B., Babcock D. F., Hille B. Dominant role of mitochondria in clearance of large Ca2+ loads from rat adrenal chromaffin cells. Neuron. 1996 Jan;16(1):219–228. doi: 10.1016/s0896-6273(00)80038-0. [DOI] [PubMed] [Google Scholar]
  28. Iino M. Biphasic Ca2+ dependence of inositol 1,4,5-trisphosphate-induced Ca release in smooth muscle cells of the guinea pig taenia caeci. J Gen Physiol. 1990 Jun;95(6):1103–1122. doi: 10.1085/jgp.95.6.1103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jouaville L. S., Ichas F., Holmuhamedov E. L., Camacho P., Lechleiter J. D. Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes. Nature. 1995 Oct 5;377(6548):438–441. doi: 10.1038/377438a0. [DOI] [PubMed] [Google Scholar]
  30. Karma Alain. Electrical alternans and spiral wave breakup in cardiac tissue. Chaos. 1994 Sep;4(3):461–472. doi: 10.1063/1.166024. [DOI] [PubMed] [Google Scholar]
  31. Kasai H., Augustine G. J. Cytosolic Ca2+ gradients triggering unidirectional fluid secretion from exocrine pancreas. Nature. 1990 Dec 20;348(6303):735–738. doi: 10.1038/348735a0. [DOI] [PubMed] [Google Scholar]
  32. Lechleiter J. D., Clapham D. E. Molecular mechanisms of intracellular calcium excitability in X. laevis oocytes. Cell. 1992 Apr 17;69(2):283–294. doi: 10.1016/0092-8674(92)90409-6. [DOI] [PubMed] [Google Scholar]
  33. Lechleiter J. D., John L. M., Camacho P. Ca2+ wave dispersion and spiral wave entrainment in Xenopus laevis oocytes overexpressing Ca2+ ATPases. Biophys Chem. 1998 May 5;72(1-2):123–129. doi: 10.1016/s0301-4622(98)00128-8. [DOI] [PubMed] [Google Scholar]
  34. Lechleiter J., Girard S., Clapham D., Peralta E. Subcellular patterns of calcium release determined by G protein-specific residues of muscarinic receptors. Nature. 1991 Apr 11;350(6318):505–508. doi: 10.1038/350505a0. [DOI] [PubMed] [Google Scholar]
  35. Lechleiter J., Girard S., Peralta E., Clapham D. Spiral calcium wave propagation and annihilation in Xenopus laevis oocytes. Science. 1991 Apr 5;252(5002):123–126. doi: 10.1126/science.2011747. [DOI] [PubMed] [Google Scholar]
  36. Li W., Llopis J., Whitney M., Zlokarnik G., Tsien R. Y. Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression. Nature. 1998 Apr 30;392(6679):936–941. doi: 10.1038/31965. [DOI] [PubMed] [Google Scholar]
  37. Li Y. X., Rinzel J. Equations for InsP3 receptor-mediated [Ca2+]i oscillations derived from a detailed kinetic model: a Hodgkin-Huxley like formalism. J Theor Biol. 1994 Feb 21;166(4):461–473. doi: 10.1006/jtbi.1994.1041. [DOI] [PubMed] [Google Scholar]
  38. Loomis W. F. Biochemistry of Aggregation in Dictyostelium. A review. Dev Biol. 1979 May;70(1):1–12. doi: 10.1016/0012-1606(79)90002-2. [DOI] [PubMed] [Google Scholar]
  39. Magnus G., Keizer J. Minimal model of beta-cell mitochondrial Ca2+ handling. Am J Physiol. 1997 Aug;273(2 Pt 1):C717–C733. doi: 10.1152/ajpcell.1997.273.2.C717. [DOI] [PubMed] [Google Scholar]
  40. Magnus G., Keizer J. Model of beta-cell mitochondrial calcium handling and electrical activity. I. Cytoplasmic variables. Am J Physiol. 1998 Apr;274(4 Pt 1):C1158–C1173. doi: 10.1152/ajpcell.1998.274.4.C1158. [DOI] [PubMed] [Google Scholar]
  41. Magnus G., Keizer J. Model of beta-cell mitochondrial calcium handling and electrical activity. II. Mitochondrial variables. Am J Physiol. 1998 Apr;274(4 Pt 1):C1174–C1184. doi: 10.1152/ajpcell.1998.274.4.C1174. [DOI] [PubMed] [Google Scholar]
  42. Marinos E., Billett F. S. Mitochondrial number, cytochrome oxidase and succinic dehydrogenase activity in Xenopus laevis oocytes. J Embryol Exp Morphol. 1981 Apr;62:395–409. [PubMed] [Google Scholar]
  43. Marinos E. The number of mitochondria in Xenopus laevis ovulated oocytes. Cell Differ. 1985 Apr;16(2):139–143. doi: 10.1016/0045-6039(85)90527-5. [DOI] [PubMed] [Google Scholar]
  44. Nathanson M. H., Burgstahler A. D., Mennone A., Fallon M. B., Gonzalez C. B., Saez J. C. Ca2+ waves are organized among hepatocytes in the intact organ. Am J Physiol. 1995 Jul;269(1 Pt 1):G167–G171. doi: 10.1152/ajpgi.1995.269.1.G167. [DOI] [PubMed] [Google Scholar]
  45. Newman E. A., Zahs K. R. Calcium waves in retinal glial cells. Science. 1997 Feb 7;275(5301):844–847. doi: 10.1126/science.275.5301.844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Parker I., Ivorra I. Inhibition by Ca2+ of inositol trisphosphate-mediated Ca2+ liberation: a possible mechanism for oscillatory release of Ca2+. Proc Natl Acad Sci U S A. 1990 Jan;87(1):260–264. doi: 10.1073/pnas.87.1.260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Pozzan T., Rizzuto R., Volpe P., Meldolesi J. Molecular and cellular physiology of intracellular calcium stores. Physiol Rev. 1994 Jul;74(3):595–636. doi: 10.1152/physrev.1994.74.3.595. [DOI] [PubMed] [Google Scholar]
  48. Putney J. W., Jr, Bird G. S. The inositol phosphate-calcium signaling system in nonexcitable cells. Endocr Rev. 1993 Oct;14(5):610–631. doi: 10.1210/edrv-14-5-610. [DOI] [PubMed] [Google Scholar]
  49. Rizzuto R., Brini M., Murgia M., Pozzan T. Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science. 1993 Oct 29;262(5134):744–747. doi: 10.1126/science.8235595. [DOI] [PubMed] [Google Scholar]
  50. 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]
  51. Robb-Gaspers L. D., Thomas A. P. Coordination of Ca2+ signaling by intercellular propagation of Ca2+ waves in the intact liver. J Biol Chem. 1995 Apr 7;270(14):8102–8107. doi: 10.1074/jbc.270.14.8102. [DOI] [PubMed] [Google Scholar]
  52. Sanderson M. J., Charles A. C., Boitano S., Dirksen E. R. Mechanisms and function of intercellular calcium signaling. Mol Cell Endocrinol. 1994 Jan;98(2):173–187. doi: 10.1016/0303-7207(94)90136-8. [DOI] [PubMed] [Google Scholar]
  53. Satoh T., Ross C. A., Villa A., Supattapone S., Pozzan T., Snyder S. H., Meldolesi J. The inositol 1,4,5,-trisphosphate receptor in cerebellar Purkinje cells: quantitative immunogold labeling reveals concentration in an ER subcompartment. J Cell Biol. 1990 Aug;111(2):615–624. doi: 10.1083/jcb.111.2.615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Scarpa A., Graziotti P. Mechanisms for intracellular calcium regulation in heart. I. Stopped-flow measurements of Ca++ uptake by cardiac mitochondria. J Gen Physiol. 1973 Dec;62(6):756–772. doi: 10.1085/jgp.62.6.756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Tang Y., Othmer H. G. A model of calcium dynamics in cardiac myocytes based on the kinetics of ryanodine-sensitive calcium channels. Biophys J. 1994 Dec;67(6):2223–2235. doi: 10.1016/S0006-3495(94)80707-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Tang Y., Stephenson J. L. Calcium dynamics and homeostasis in a mathematical model of the principal cell of the cortical collecting tubule. J Gen Physiol. 1996 Feb;107(2):207–230. doi: 10.1085/jgp.107.2.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Tang Y., Stephenson J. L., Othmer H. G. Simplification and analysis of models of calcium dynamics based on IP3-sensitive calcium channel kinetics. Biophys J. 1996 Jan;70(1):246–263. doi: 10.1016/S0006-3495(96)79567-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Thomas A. P., Bird G. S., Hajnóczky G., Robb-Gaspers L. D., Putney J. W., Jr Spatial and temporal aspects of cellular calcium signaling. FASEB J. 1996 Nov;10(13):1505–1517. [PubMed] [Google Scholar]
  59. Thomas A. P., Robb-Gaspers L. D., Rooney T. A., Hajnóczky G., Renard-Rooney D. C., Lin C. Spatial organization of oscillating calcium signals in liver. Biochem Soc Trans. 1995 Aug;23(3):642–648. doi: 10.1042/bst0230642. [DOI] [PubMed] [Google Scholar]
  60. Tsien R. W., Tsien R. Y. Calcium channels, stores, and oscillations. Annu Rev Cell Biol. 1990;6:715–760. doi: 10.1146/annurev.cb.06.110190.003435. [DOI] [PubMed] [Google Scholar]
  61. Wagner J., Li Y. X., Pearson J., Keizer J. Simulation of the fertilization Ca2+ wave in Xenopus laevis eggs. Biophys J. 1998 Oct;75(4):2088–2097. doi: 10.1016/S0006-3495(98)77651-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Wang S. S., Augustine G. J. Confocal imaging and local photolysis of caged compounds: dual probes of synaptic function. Neuron. 1995 Oct;15(4):755–760. doi: 10.1016/0896-6273(95)90167-1. [DOI] [PubMed] [Google Scholar]
  63. Yao Y., Parker I. Ca2+ influx modulation of temporal and spatial patterns of inositol trisphosphate-mediated Ca2+ liberation in Xenopus oocytes. J Physiol. 1994 Apr 1;476(1):17–28. [PMC free article] [PubMed] [Google Scholar]

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