Mitochondria Na+-Ca2+ Exchange in Cardiomyocytes and Lymphocytes

  • Bongju Kim
  • Ayako Takeuchi
  • Orie Koga
  • Masaki Hikida
  • Satoshi MatsuokaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 961)


Mitochondria Na+-Ca2+ exchange (NCXmit) was first discovered by Carafoli et al. in 1974. Thereafter, the mechanisms and roles of NCXmit have been extensively studied. We review NCXmit in cardiomyocytes and lymphocytes by presenting our recent studies on it. Studies of NCXmit in rat ventricular cells demonstrated that NCXmit is voltage dependent and electrogenic. A targeted knockdown and knockout of NCLX in HL-1 cardiomyocytes and B lymphocytes, respectively, significantly reduced the NCXmit activity, indicating that NCLX is a major component of NCXmit in these cells. The store-operated Ca2+ entry was greatly attenuated in NCLX knockout lymphocytes, suggesting that substantial amount of Ca2+ enters into mitochondria and is released to cytosol via NCXmit. NCXmit or NCLX has pivotal roles in Ca2+ handling in mitochondria and cytoplasm.


Mitochondrial NCX Calcium Voltage dependence Electrogenicity NCLX Lymphocytes Cardiomyocytes Store-operated Ca2+ entry 


  1. H. Affolter, E. Carafoli, The Ca2+-Na+ antiporter of heart mitochondria operates electroneutrally. Biochem. Biophys. Res. Commun. 95, 193–196 (1980)PubMedCrossRefGoogle Scholar
  2. S. Arnaudeau, W.L. Kelley, J.V. Walsh Jr., N. Demaurex, Mitochondria recycle Ca2+ to the endoplasmic reticulum and prevent the depletion of neighboring endoplasmic reticulum regions. J. Biol. Chem. 276, 29430–29439 (2001)PubMedCrossRefGoogle Scholar
  3. E. Barth, G. Stämmler, B. Speiser, J. Schaper, Ultrastructural quantitation of mitochondria and myofilaments in cardiac muscle from 10 different animal species including man. J. Mol. Cell. Cardiol. 24, 669–681 (1992)PubMedCrossRefGoogle Scholar
  4. J.M. Baughman, F. Perocchi, H.S. Girgis, M. Plovanich, C.A. Belcher-Timme, Y. Sancak, X.R. Bao, L. Strittmatter, O. Goldberger, R.L. Bogorad, V. Koteliansky, V.K. Mootha, Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011)PubMedCrossRefGoogle Scholar
  5. C.J. Bell, N.A. Bright, G.A. Rutter, E.J. Griffiths, ATP regulation in adult rat cardiomyocytes: time-resolved decoding of rapid mitochondrial calcium spiking imaged with targeted photoproteins. J. Biol. Chem. 281, 28058–28067 (2006)PubMedCrossRefGoogle Scholar
  6. P. Bernardi, Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol. Rev. 79, 1127–1155 (1999)PubMedGoogle Scholar
  7. M.P. Blaustein, W.J. Lederer, Sodium/calcium exchange: its physiological implications. Physiol. Rev. 79, 763–854 (1999)PubMedGoogle Scholar
  8. M.D. Brand, The stoichiometry of the exchange catalysed by the mitochondrial calcium/sodium antiporter. Biochem. J. 229, 161–166 (1985)PubMedGoogle Scholar
  9. X. Cai, J. Lytton, Molecular cloning of a sixth member of the K+-dependent Na+/Ca2+ exchanger gene family, NCKX6. J. Biol. Chem. 279, 5867–5876 (2004)PubMedCrossRefGoogle Scholar
  10. E. Carafoli, The fateful encounter of mitochondria with calcium: how did it happen? Biochim. Biophys. Acta 1797, 595–606 (2010)PubMedCrossRefGoogle Scholar
  11. E. Carafoli, R. Tiozzo, G. Lugli, F. Crovetti, C. Kratzing, The release of calcium from heart mitochondria by sodium. J. Mol. Cell. Cardiol. 6, 361–371 (1974)PubMedCrossRefGoogle Scholar
  12. F. Celsi, P. Pizzo, M. Brini, S. Leo, C. Fotino, P. Pinton, R. Rizzuto, Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. Biochim. Biophys. Acta 1787, 335–344 (2009)PubMedCrossRefGoogle Scholar
  13. W.C. Claycomb, N.A. Lanson Jr., B.S. Stallworth, D.B. Egeland, J.B. Delcarpio, A. Bahinski, N.J. Izzo Jr., HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc. Natl. Acad. Sci. U. S. A. 95, 2979–2984 (1998)PubMedCrossRefGoogle Scholar
  14. S. Cortassa, M.A. Aon, B. O’Rourke, R. Jacques, H.J. Tseng, E. Marbán, R.L. Winslow, A computational model integrating electrophysiology, contraction, and mitochondrial bioenergetics in the ventricular myocyte. Biophys. J. 91, 1564–1589 (2006)PubMedCrossRefGoogle Scholar
  15. D.A. Cox, M.A. Matlib, A role for the mitochondrial Na+-Ca2+ exchanger in the regulation of oxidative phosphorylation in isolated heart mitochondria. J. Biol. Chem. 268, 938–947 (1993)PubMedGoogle Scholar
  16. M. Crompton, M. Capano, E. Carafoli, The sodium induced efflux of calcium from heart mitochondria. A possible mechanism for the regulation of mitochondrial calcium. Eur. J. Biochem. 69, 453–462 (1976)CrossRefGoogle Scholar
  17. M. Crompton, M. Künzi, E. Carafoli, The calcium-induced and sodium-induced effluxes of calcium from heart mitochondria. Evidence for a sodium-calcium carrier. Eur. J. Biochem. 79, 549–558 (1977)PubMedCrossRefGoogle Scholar
  18. M. Crompton, R. Moser, H. Lüdi, E. Carafoli, The interrelations between the transport of sodium and calcium in mitochondria of various mammalian tissues. Eur. J. Biochem. 82, 25–31 (1978)PubMedCrossRefGoogle Scholar
  19. G. Csordás, G. Hajnóczky, SR/ER-mitochondrial local communication: calcium and ROS. Biochim. Biophys. Acta 1787, 1352–1362 (2009)PubMedCrossRefGoogle Scholar
  20. H.F. DeLuca, G.W. Engstrom, Calcium uptake by rat kidney mitochondria. Proc. Natl. Acad. Sci. U. S. A. 47, 1744–1750 (1961)PubMedCrossRefGoogle Scholar
  21. S. Despa, M.A. Islam, S.M. Pogwizd, D.M. Bers, Intracellular [Na+] and Na+ pump rate in rat and rabbit ventricular myocytes. J. Physiol. 539, 133–143 (2002)PubMedCrossRefGoogle Scholar
  22. R. DiPolo, L. Beaugé, Sodium/calcium exchanger: influence of metabolic regulation on ion carrier interactions. Physiol. Rev. 86, 155–203 (2006)PubMedCrossRefGoogle Scholar
  23. A.E. Doering, D.A. Nicoll, Y. Lu, L. Lu, J.N. Weiss, K.D. Philipson, Topology of a functionally important region of the cardiac Na+/Ca2+ exchanger. J. Biol. Chem. 273, 778–783 (1998)PubMedCrossRefGoogle Scholar
  24. S. Feske, Calcium signalling in lymphocyte activation and disease. Nat. Rev. Immunol. 7, 690–702 (2007)PubMedCrossRefGoogle Scholar
  25. P. Gobbi, P. Castaldo, A. Minelli, S. Salucci, S. Magi, E. Corcione, S. Amoroso, Mitochondrial localization of Na+/Ca2+ exchangers NCX1-3 in neurons and astrocytes of adult rat brain in situ. Pharmacol. Res. 56, 556–565 (2007)PubMedCrossRefGoogle Scholar
  26. L.H. Hayat, M. Crompton, Evidence for the existence of regulatory sites for Ca2+ on the Na+/Ca2+ carrier of cardiac mitochondria. Biochem. J. 202, 509–518 (1982)PubMedGoogle Scholar
  27. M. Hoth, C.M. Fanger, R.S. Lewis, Mitochondrial regulation of store-operated calcium signaling in T lymphocytes. J. Cell Biol. 137, 633–648 (1997)PubMedCrossRefGoogle Scholar
  28. D. Jiang, L. Zhao, D.E. Clapham, Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 326, 144–147 (2009)PubMedCrossRefGoogle Scholar
  29. H. Jo, A. Noma, S. Matsuoka, Calcium-mediated coupling between mitochondrial substrate dehydrogenation and cardiac workload in single guinea-pig ventricular myocytes. J. Mol. Cell. Cardiol. 40, 394–404 (2006)PubMedCrossRefGoogle Scholar
  30. D.W. Jung, K. Baysal, G.P. Brierley, The sodium-calcium antiport of heart mitochondria is not electroneutral. J. Biol. Chem. 270, 672–678 (1995)PubMedCrossRefGoogle Scholar
  31. B. Kim, S. Matsuoka, Cytoplasmic Na+-dependent modulation of mitochondrial Ca2+ via electrogenic mitochondrial Na+-Ca2+ exchange. J. Physiol. 586, 1683–1697 (2008)PubMedCrossRefGoogle Scholar
  32. B. Kim, A. Takeuchi, O. Koga, M. Hikida, S. Matsuoka, Pivotal role of mitochondrial Na+-Ca2+ exchange in antigen receptor mediated Ca2+ signalling in DT40 and A20 B lymphocytes. J. Physiol. (2012 in press) Google Scholar
  33. Y. Kirichok, G. Krapivinsky, D.E. Clapham, The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360–364 (2004)PubMedCrossRefGoogle Scholar
  34. R. Malli, M. Frieden, M. Trenker, W.F. Graier, The role of mitochondria for Ca2+ refilling of the endoplasmic reticulum. J. Biol. Chem. 280, 12114–12122 (2005)PubMedCrossRefGoogle Scholar
  35. S. Matsuoka, D.W. Hilgemann, Inactivation of outward Na+-Ca2+ exchange current in guinea-pig ventricular myocytes. J. Physiol. 476, 443–458 (1994)Google Scholar
  36. J.G. McCormack, A.P. Halestrap, R.M. Denton, Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol. Rev. 70, 391–425 (1990)PubMedGoogle Scholar
  37. C.C. Mendes, D.A. Gomes, M. Thompson, N.C. Souto, T.S. Goes, A.M. Goes, M.A. Rodrigues, M.V. Gomez, M.H. Nathanson, M.F. Leite, The type III inositol 1,4,5-trisphosphate receptor preferentially transmits apoptotic Ca2+ signals into mitochondria. J. Biol. Chem. 280, 40892–40900 (2005)PubMedCrossRefGoogle Scholar
  38. M. Murgia, C. Giorgi, P. Pinton, R. Rizzuto, Controlling metabolism and cell death: at the heart of mitochondrial calcium signalling. J. Mol. Cell. Cardiol. 46, 781–788 (2009)PubMedCrossRefGoogle Scholar
  39. R. Palty, E. Ohana, M. Hershfinkel, M. Volokita, V. Elgazar, O. Beharier, W.F. Silverman, M. Argaman, I. Sekler, Lithium-calcium exchange is mediated by a distinct potassium-independent sodium-calcium exchanger. J. Biol. Chem. 279, 25234–25240 (2004)PubMedCrossRefGoogle Scholar
  40. R. Palty, W.F. Silverman, M. Hershfinkel, T. Caporale, S.L. Sensi, J. Parnis, C. Nolte, D. Fishman, V. Shoshan-Barmatz, S. Herrmann, D. Khananshvili, I. Sekler, NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc. Natl. Acad. Sci. U. S. A. 107, 436–441 (2010)PubMedCrossRefGoogle Scholar
  41. A.B. Parekh, Mitochondrial regulation of store-operated CRAC channels. Cell Calcium 44, 6–13 (2008)PubMedCrossRefGoogle Scholar
  42. P. Paucek, M. Jabůrek, Kinetics and ion specificity of Na+/Ca2+ exchange mediated by the reconstituted beef heart mitochondrial Na+/Ca2+ antiporter. Biochim. Biophys. Acta 1659, 83–91 (2004)PubMedCrossRefGoogle Scholar
  43. F. Perocchi, V.M. Gohil, H.S. Girgis, X.R. Bao, J.E. McCombs, A.E. Palmer, V.K. Mootha, MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 467, 291–296 (2010)PubMedCrossRefGoogle Scholar
  44. G.E. Petrzilka, H.E. Schroeder, Activation of human T-lymphocytes. A kinetic and stereological study. Cell Tissue Res. 201, 101–127 (1979)PubMedCrossRefGoogle Scholar
  45. D. Poburko, C.H. Liao, C. van Breemen, N. Demaurex, Mitochondrial regulation of sarcoplasmic reticulum Ca2+ content in vascular smooth muscle cells. Circ. Res. 104, 104–112 (2009)PubMedCrossRefGoogle Scholar
  46. A. Quintana, C. Schwindling, A.S. Wenning, U. Becherer, J. Rettig, E.C. Schwarz, M. Hoth, T cell activation requires mitochondrial translocation to the immunological synapse. Proc. Natl. Acad. Sci. U. S. A. 104, 14418–14423 (2007)PubMedCrossRefGoogle Scholar
  47. S.Y. Ryu, G. Beutner, R.T. Dirksen, K.W. Kinnally, S.S. Sheu, Mitochondrial ryanodine receptors and other mitochondrial Ca2+ permeable channels. FEBS Lett. 584, 1948–1955 (2010)PubMedCrossRefGoogle Scholar
  48. V.K. Sharma, V. Ramesh, C. Franzini-Armstrong, S.S. Sheu, Transport of Ca2+ from sarcoplasmic reticulum to mitochondria in rat ventricular myocytes. J. Bioenerg. Biomembr. 32, 97–104 (2000)PubMedCrossRefGoogle Scholar
  49. G. Szabadkai, K. Bianchi, P. Várnai, D. De Stefani, M.R. Wieckowski, D. Cavagna, A.I. Nagy, T. Balla, R. Rizzuto, Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J. Cell Biol. 175, 901–911 (2006)PubMedCrossRefGoogle Scholar
  50. P.R. Territo, S.A. French, M.C. Dunleavy, F.J. Evans, R.S. Balaban, Calcium activation of heart mitochondrial oxidative phosphorylation: rapid kinetics of mVO2, NADH, AND light scattering. J. Biol. Chem. 276, 2586–2599 (2001)PubMedCrossRefGoogle Scholar
  51. M. Vig, J.P. Kinet, Calcium signaling in immune cells. Nat. Immunol. 10, 21–27 (2009)PubMedCrossRefGoogle Scholar
  52. S.M. White, P.E. Constantin, W.C. Claycomb, Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. Am. J. Physiol. Heart Circ. Physiol. 286, H823–H829 (2004)PubMedCrossRefGoogle Scholar
  53. D.E. Wingrove, T.E. Gunter, 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. 261, 15166–15171 (1986)PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Bongju Kim
    • 1
  • Ayako Takeuchi
    • 2
  • Orie Koga
    • 1
  • Masaki Hikida
    • 1
  • Satoshi Matsuoka
    • 1
    Email author
  1. 1.Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of MedicineKyoto UniversityKyotoJapan
  2. 2.Department of Physiology and Biophysics, Graduate School of MedicineKyoto UniversityKyotoJapan

Personalised recommendations