Ukr.Biochem.J. 2014; Volume 86, Issue 6, Nov-Dec, pp. 18-30


Ca ion transport in smooth muscle mitochondria

L. G. Babich, S. G. Shlykov, S. O. Kosterin

Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;

Review focuses on the analysis of literature data and own results concerning properties of mitochondria Са2+ transporting systems and their regu­lation. Three mechanisms for mitochondrial Ca2+ uptake are described: the electrogenic mitochondrial Ca2+ uniporter, a rapid mode of Ca2+ uptake (RaM) and ryanodine-sensitive Ca2+ channels (RyR). Two mechanisms of Ca2+ efflux from the mitochondrial matrix have been proposed: Na+-dependent and Na+-independent Ca2+ exchange. The mitochondrial permeability transition pore can also function as a Ca2+ efflux mechanism. Ca2+ accumulation in mitochondria resulted in an increase of mitochondrial membrane potential, ATP synthesis and activation of metabolites transport. The dissipation of mitochondrial membrane potential should prevent mitochondrial Ca2+ uptake. Our data concerning depolarizing effect of calmodulin antagonists and hyperpolarizing effect of calix[4]arenes С-136 and С-137 on the myometrium mitochondria can be applied on the demand  of mitochondria membrane potential correction.

Keywords: , ,


  1. Duchen MR. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Aspects Med. 2004 Aug;25(4):365-451. Review. PubMed, CrossRef
  2. Dedkova EN, Blatter LA. Mitochondrial Ca2+ and the heart. Cell Calcium. 2008 Jul;44(1):77-91. Review. PubMed, CrossRef
  3. Hoppe UC. Mitochondrial calcium channels. FEBS Lett. 2010 May 17;584(10):1975-81. Review. PubMed, CrossRef
  4. Santo-Domingo J, Demaurex N. Calcium uptake mechanisms of mitochondria. Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):907-12. Review. PubMed, CrossRef
  5. Gunter KK, Gunter TE. Transport of calcium by mitochondria. J Bioenerg Biomembr. 1994 Oct;26(5):471-85. Review. PubMed, CrossRef
  6. Padua RA, Baron KT, Thyagarajan B, Campbell C, Thayer SA. Reduced Ca2+ uptake by mitochondria in pyruvate dehydrogenase-deficient human diploid fibroblasts. Am J Physiol. 1998 Mar;274(3 Pt 1):C615-22. PubMed
  7. Contreras L, Drago I, Zampese E, Pozzan T. Mitochondria: the calcium connection. Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):607-18. Epub 2010 May 12. Review. PubMed, CrossRef
  8. Griffiths EJ. Mitochondrial calcium transport in the heart: physiological and pathological roles. J Mol Cell Cardiol. 2009 Jun;46(6):789-803. Epub 2009 Mar 12. Review. PubMed, CrossRef
  9. Griffiths EJ, Balaska D, Cheng WH. The ups and downs of mitochondrial calcium signalling in the heart. Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):856-64. Epub 2010 Feb 24. Review. PubMedCrossRef
  10. Calì T, Ottolini D, Brini M. Mitochondrial Ca(2+) as a key regulator of mitochondrial activities. Adv Exp Med Biol. 2012;942:53-73. Review. PubMed, CrossRef
  11. Gincel D, Zaid H, Shoshan-Barmatz V. Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function. Biochem J. 2001 Aug 15;358(Pt 1):147-55. PubMed, PubMedCentral, CrossRef
  12. Szabadkai G, Duchen MR. Mitochondria: the hub of cellular Ca2+ signaling. Physiology (Bethesda). 2008 Apr;23:84-94. Review. Erratum in: Physiology (Bethesda). 2008 Aug;23:230. PubMed, CrossRef
  13. Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N. VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med. 2010 Jun;31(3):227-85. Epub 2010 Mar 23. Review. PubMed, CrossRef
  14. Rizzuto R, Marchi S, Bonora M, Aguiari P, Bononi A, De Stefani D, Giorgi C, Leo S, Rimessi A, Siviero R, Zecchini E, Pinton P. Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochim Biophys Acta. 2009 Nov;1787(11):1342-51. Epub 2009 Mar 31. Review. PubMed, PubMedCentral, CrossRef
  15. Spät A, Szanda G, Csordás G, Hajnóczky G. High- and low-calcium-dependent mechanisms of mitochondrial calcium signalling. Cell Calcium. 2008 Jul;44(1):51-63. Epub 2008 Feb 19. Review. PubMed, PubMedCentral, CrossRef
  16. Carafoli E. The fateful encounter of mitochondria with calcium: how did it happen? Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):595-606. Epub 2010 Apr 10. Review. PubMed, CrossRef
  17. Saotome M, Katoh H, Satoh H, Nagasaka S, Yoshihara S, Terada H, Hayashi H. Mitochondrial membrane potential modulates regulation of mitochondrial Ca2+ in rat ventricular myocytes.  Am J Physiol Heart Circ Physiol. 2005 Apr;288(4):H1820-8. Epub 2004 Nov 24. PubMed, CrossRef
  18. Kim B, Matsuoka S. Cytoplasmic Na+-dependent modulation of mitochondrial Ca2+ via electrogenic mitochondrial Na+-Ca2+ exchange. Ш 2008 Mar 15;586(6):1683-97. Epub 2008 Jan 24. PubMed, PubMedCentral, CrossRef
  19. Smets I, Caplanusi A, Despa S, Molnar Z, Radu M, Vande Ven M, Ameloot M, Steels P. Ca2+ uptake in mitochondria occurs via the reverse action of the Na+/Ca2+ exchanger inmetabolically inhibitedMDCK cells. Am J Physiol Renal Physiol. 2004;286(4):F784-794.  PubMed, CrossRef
  20. Missiaen L, Wuytack F, Raeymaekers L, De Smedt H, Droogmans G, Declerck I, Casteels R. Ca2+ extrusion across plasma membrane and Ca2+ uptake by intracellular stores. Pharmacol Ther. 1991;50(2):191-232. Review. PubMed, CrossRef
  21. Gunter TE, Pfeiffer DR. Mechanisms by which mitochondria transport calcium. Am J Physiol. 1990 May;258(5 Pt 1):C755-86. Review. PubMed
  22. Kosterin S. A., Burdyga F. V. Ca2+ transport and intracellular homeostasis in myometrium. Uspekhi Sovrem. Biologii. 1993;113(4):485-506.
  23. Babich LG, Shlykov SG, Borisova LA, Kosterin SA. Energy-dependent Ca2+-transport in intracellular smooth muscle structures. Biokhimiia. 1994 Aug;59(8):1218-29. Russian. PubMed
  24. Kosterin SA. Calcium transport in smooth muscle. Kiev: Naukova dumka. 1990. 216 p. (In Russian).
  25. Batra S. Uptake and energy-dependent extrusion of calcium in the rat uterus. Acta Physiol Scand. 1982 Mar;114(3):447-52. PubMed, CrossRef
  26. Carafoli E. Intracellular calcium regulation, with special attention to the role of the plasma membrane calcium pump. J Cardiovasc Pharmacol. 1988;12(Suppl 3):S77-84. Review. PubMed, CrossRef
  27. Palade P, Dettbarn C, Brunder D, Stein P, Hals G. Pharmacology of calcium release from sarcoplasmic reticulum. J Bioenerg Biomembr. 1989 Apr;21(2):295-320. Review. PubMed, CrossRef
  28. Wingrove DE, Gunter TE. Kinetics of mitochondrial calcium transport. II. A kinetic description of the sodium-dependent calcium efflux mechanism of liver mitochondria and inhibition by ruthenium red and by tetraphenylphosphonium. J Biol Chem. 1986 Nov 15;261(32):15166-71. PubMed
  29. Akerman KE. Effect of Mg2+ and spermine on the kinetics of Ca2+ transport in rat-liver mitochondria. J Bioenerg Biomembr. 1977 Feb;9(1):65-72. PubMed, CrossRef
  30. Tassani V, Campagnolo M, Toninello A, Siliprandi D. The contribution of endogenous polyamines to the permeability transition of rat liver mitochondria. Biochem Biophys Res Commun. 1996 Sep 24;226(3):850-4. PubMed, CrossRef
  31. Babich LG, Borisova LA, Shlykov SG, Titus OV, Kosterin SA. Effect of Mg ions and spermine on ATP-dependent Ca2+ transport in myometrial intracellular structures. I. Comparative study of Ca2+ accumulation in mitochondria and sarcoplasmic reticulum. Ukr Biokhim Zhurn. 2004;76(5):52-60. (In Russian). PubMed
  32. Babich LG, Borisova LA, Shlykov SG, Titus OV., Kosterin SA. Effect of Mg ions and spermine on ATP-dependent Ca2+ transport in myometrial intracellular structures. II. Comparative study of spermine, Mg ions and cyclosporine A effects on Ca2+ transport in mitochondria. Ukr Biokhim Zhurn. 2004;76(6):55-62. (In Russian). PubMed
  33. Aziz SM, Olson JW, Gillespie MN. Multiple polyamine transport pathways in cultured pulmonary artery smooth muscle cells: regulation by hypoxia. Am J Respir Cell Mol Biol. 1994 Feb;10(2):160-6. PubMed, CrossRef
  34. Löser C. Polyamines in human and animal milk. Br J Nutr. 2000 Nov;84(S1):S55-8. Review. PubMed, CrossRef
  35. Fernández AI, Cantabrana B, Sánchez M, Hidalgo A. Extracellular and intracellular effects of polyamines on smooth muscle contractions. Life Sci. 1995;57(9):855-61. PubMed, CrossRef
  36. Lukyanenko V, Chikando A, Lederer WJ. Mitochondria in cardiomyocyte Ca2+ signaling. Int J Biochem Cell Biol. 2009 Oct;41(10):1957-71. Epub 2009 Apr 2. Review. PubMedPubMedCentral, CrossRef
  37. Buntinas L, Gunter KK, Sparagna GC, Gunter TE. The rapid mode of calcium uptake into heart mitochondria (RaM): comparison to RaM in liver mitochondria. Biochim Biophys Acta. 2001 Apr 2;1504(2-3):248-61. PubMed, CrossRef
  38. Gunter TE, Sheu SS. Characteristics and possible functions of mitochondrial Ca(2+) transport mechanisms. Biochim Biophys Acta. 2009 Nov;1787(11):1291-308. Review. PubMed, PubMedCentral, CrossRef
  39. Altschafl BA, Beutner G, Sharma VK, Sheu SS, Valdivia HH. The mitochondrial ryanodine receptor in rat heart: a pharmaco-kinetic profile. Biochim Biophys Acta. 2007;1768(7)1784-1795. PubMed, CrossRef
  40. Beutner G, Sharma VK, Giovannucci DR, Yule DI, Sheu SS. Identification of a ryanodine receptor in rat heart mitochondria. J Biol Chem. 2001 Jun 15;276(24):21482-8. PubMed, CrossRef
  41. Beutner G, Sharma VK, Lin L, Ryu SY, Dirksen RT, Sheu SS. Type 1 ryanodine receptor in cardiac mitochondria: transducer of excitation-metabolism coupling. Biochim Biophys Acta. 2005 Nov 10;1717(1):1-10. PubMed, CrossRef
  42. Babich LH, Shlykov SH, Kandaurova NV, Kosterin SA. Transmembrane Ca2+ exchange in depolarized rat myometrium mitochondria. Ukr Biokhim Zhurn. 2011;83(6):56-62. (In Russian). PubMed
  43. Nicholls DG. Mitochondria and calcium signaling. Cell Calcium. 2005 Sep-Oct;38(3-4):311-7. Review. PubMed, CrossRef
  44. Murphy E, Eisner DA. Regulation of intracellular and mitochondrial sodium in health and disease. Circ Res. 2009 Feb 13;104(3):292-303. Review. PubMed, PubMedCentral, CrossRef
  45. Despa S, Islam MA, Pogwizd SM, Bers DM. Intracellular [Na+] and Na+ pump rate in rat and rabbit ventricular myocytes. J Physiol. 2002 Feb 15;539(Pt 1):133-43. PubMed, PubMedCentral, CrossRef
  46. Nicholls D, Akerman K. Mitochondrial calcium transport. Biochim Biophys Acta. 1982 Sep 1;683(1):57-88. Review. PubMed, CrossRef
  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. Review. PubMed
  48. Bernardi P, Vassanelli S, Veronese P, Colonna R, Szabó I, Zoratti M. Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations. J Biol Chem. 1992 Feb 15;267(5):2934-9. PubMed
  49. Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999 Jul 15;341(Pt 2):233-49. Review. PubMed, PubMedCentral, CrossRef
  50. Leung AW, Halestrap AP. Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):946-52. Review. PubMed, CrossRef
  51. Starkov AA. The molecular identity of the mitochondrial Ca2+ sequestration system. FEBS J. 2010 Sep;277(18):3652-63. Review. PubMed, PubMedCentral, CrossRef
  52. Rizzuto R, Pozzan T. Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev. 2006 Jan;86(1):369-408. Review. PubMed, CrossRef
  53. Gunter TE, Gunter KK, Sheu SS, Gavin CE. Mitochondrial calcium transport: physiological and pathological relevance. Am J Physiol. 1994 Aug;267(2 Pt 1):C313-39. Review. PubMed
  54. Hansford RG. Physiological role of mitochondrial Ca2+ transport. J Bioenerg Biomembr. 1994 Oct;26(5):495-508. Review. PubMed, CrossRef
  55. Satrústegui J, Pardo B, Del Arco A. Mitochondrial transporters as novel targets for intracellular calcium signaling. Physiol Rev. 2007 Jan;87(1):29-67. Review. PubMed, CrossRef
  56. Yamamoto H, van Breemen C. Ca2+ compartments in saponin-skinned cultured vascular smooth muscle cells. J Gen Physiol. 1986 Mar;87(3):369-89. Review. PubMed, PubMedCentral, CrossRef
  57. Griffiths EJ, Rutter GA. Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells. Biochim Biophys Acta. 2009 Nov;1787(11):1324-33. Epub 2009 Feb 3. Review. PubMed, CrossRef
  58. McCormack JG, Halestrap AP, Denton RM. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev. 1990 Apr;70(2):391-425. Review. PubMed
  59. Rizzuto R, Simpson AW, Brini M, Pozzan T. Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature. 1992 Jul 23;358(6384):325-7.  PubMed, CrossRef
  60. 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):744-7. PubMed, CrossRef
  61. Velykopols’ka OIu, Man’ko BO, Man’ko VV. Endoplasmic-mitochondrial Ca(2+)-functional unit: dependence of respiration of secretory cells on activity of ryanodine- and IP3 – sensitive Ca(2+)-channels. Ukr Biokhim Zhurn. 2012 Sep-Oct;84(5):76-88. Ukrainian. PubMed
  62. Vance J. E. MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond.  Biochim Biophys Acta. 2014 Apr 4;1841(4):595-609. PubMed, CrossRef
  63. Marchi S, Patergnani S, Pinton P. The endoplasmic reticulum-mitochondria connection: one touch, multiple functions. Biochim Biophys Acta. 2014 Apr;1837(4):461-9.  Review. PubMed, CrossRef
  64. Walsh C, Barrow S, Voronina S, Chvanov M, Petersen OH, Tepikin A. Modulation of calcium signalling by mitochondria. Biochim Biophys Acta. 2009 Nov;1787(11):1374-82. Epub 2009 Jan 22. Review. PubMedCrossRef
  65. Poburko D, Santo-Domingo J, Demaurex N. Dynamic regulation of the mitochondrial proton gradient during cytosolic calcium elevations. J Biol Chem. 2011 Apr 1;286(13):11672-84. PubMed, PubMedCentral, CrossRef
  66. Wu X, Bers DM. Free and bound intracellular calmodulin measurements in cardiac myocytes. Cell Calcium. 2007 Apr;41(4):353-64. PubMedPubMedCentral, CrossRef
  67. Means AR, VanBerkum MF, Bagchi I, Lu KP, Rasmussen CD. Regulatory functions of calmodulin. Pharmacol Ther. 1991;50(2):255-70. Review. PubMed, CrossRef
  68. Vogel HJ. The Merck Frosst Award Lecture 1994. Calmodulin: a versatile calcium mediator protein. Biochem Cell Biol. 1994 Sep-Oct;72(9-10):357-76. Review. PubMed, CrossRef
  69. James P, Vorherr T, Carafoli E. Calmodulin-binding domains: just two faced or multi-faceted? Trends Biochem Sci. 1995 Jan;20(1):38-42. PubMed, CrossRef
  70. Maier LS, Bers DM. Calcium, calmodulin, and calcium-calmodulin kinase II: heartbeat to heartbeat and beyond. J Mol Cell Cardiol. 2002 Aug;34(8):919-39. Review. PubMed, CrossRef
  71. Moreau B, Nelson C, Parekh AB. Biphasic regulation of mitochondrial Ca2+ uptake by cytosolic Ca2+ concentration. Curr Biol. 2006 Aug 22;16(16):1672-7. PubMed, CrossRef
  72. Babich LH, Shlykov SH, Naumova NV, Kosterin SO. Use of flow cytometry to determine Ca2+ content in mitochondria and influence of calmodulin antagonists on it. Ukr Biokhim Zhurn. 2008 Jul-Aug;80(4):51-8. Ukrainian. PubMed
  73. Shlykov SH, Babich LH, Ievtushenko MIe, Karakhim SO, Kosterin SO. Modulation of myometrium mitochondrial membrane potential by calmodulin antagonists. Ukr Biochem J. 2014 Jan-Feb;86(1):29-41. Ukrainian. PubMed
  74. Divakaruni AS, Brand MD. The regulation and physiology of mitochondrial proton leak. Physiology (Bethesda). 2011 Jun;26(3):192-205. Review. PubMed, CrossRef
  75. Scatena R. Mitochondria and drugs. Adv Exp Med Biol. 2012;942:329-46. Review. PubMedCrossRef
  76. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995 Mar 10;267(5203):1456-62. Review. PubMed
  77. Skulachev VP. Bioenergetic aspects of apoptosis, necrosis and mitoptosis. Apoptosis. 2006 Apr;11(4):473-85. Review. PubMed
  78. Giovannini C, Matarrese P, Scazzocchio B, Sanchez M, Masella R, Malorni W. Mitochondria hyperpolarization is an early event in oxidized low-density lipoprotein-induced apoptosis in Caco-2 intestinal cells. FEBS Lett. 2002 Jul 17;523(1-3):200-6. PubMed
  79. Sommer SP, Sommer S, Sinha B, Wiedemann J, Otto C, Aleksic I, Schimmer C, Leyh RG. Ischemia-reperfusion injury-induced pulmonary mitochondrial damage. J Heart Lung Transplant. 2011 Jul;30(7):811-8. PubMed, CrossRef
  80. Gutsche C. D. Calixarenes Revisited. The Royal Society of Chemistry: Cambridge. 1998.
  81. Gutshe C. D., Igbal M. p-tert-Butyl calix[4]arene. Org. Synth. 1990;68:234-236.
  82. Rodik RV, Boyko VI, Kalchenko VI. Calixarenes in bio-medical researches. Curr Med Chem. 2009;16(13):1630-55. Review. PubMed, CrossRef
  83. Klyachina MА, Boyko VІ, Yakovenko AV, Babich LG, Shlykov SG, Kosterin SО, Khilya VP, Kalchenko VI. Calix[4]arene N-Сhalconeamides: synthesis and influence on Mg2+,АТP-Dependent Са2+ accumulation in the smooth muscle subcellular structures. J Inclusion Phenom Macrocyclic Chem. 2008 Jan;60(1-2):131-137. CrossRef
  84. Babich LG, Shlykov SG, Boyko VI, Klyachina MA, Kosterin SA. Calix[4]arenes C-136 and C-137 hyperpolarize myometrium mitochondria membranes. Russian J Bioorg Chem. 2013 Nov-Dec;39(6):728-35. Russian. PubMed

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