Biochemistry (Moscow)

, Volume 84, Issue 6, pp 593–607 | Cite as

Mitochondrial Ca2+ Transport: Mechanisms, Molecular Structures, and Role in Cells

  • K. N. BelosludtsevEmail author
  • M. V. Dubinin
  • N. V. Belosludtseva
  • G. D. Mironova


Mitochondria are among the most important cell organelles involved in the regulation of intracellular calcium homeostasis. During the last decade, a number of molecular structures responsible for the mitochondrial calcium transport have been identified including the mitochondrial Ca2+ uniporter (MCU), Na+/Ca2+ exchanger (NCLX), and Ca2+/H+ antiporter (Letm1). The review summarizes the data on the structure, regulation, and physiological role of such structures. The pathophysiological mechanism of Ca2+ transport through the cyclosporine A-sensitive mitochondrial permeability transition pore is discussed. An alternative mechanism for the mitochondrial pore opening, namely, formation of the lipid pore induced by saturated fatty acids, and its role in Ca2+ transport are described in detail.


mitochondria Ca2+ transport MCU NCLX MPT pore mitochondrial pore lipid pore 



endoplasmic reticulum


inner mito-chondrial membrane


inositol 1,4,5-triphosphate


Ca2+/H+ antiporter


mitochondria-associated membrane


mitochondrial Ca2+ uniporter


mito-chondrial calcium uptake




pore mito-chondrial permeability transition pore


Na+/Ca2+ exchanger


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  1. 1.
    Deluca, H. F., and Engstrom, G. W. (1961) Calcium uptake by rat kidney mitochondria, Proc. Natl. Acad. Sci. USA, 47, 1744–1750, doi: Scholar
  2. 2.
    Vasington, F. D., and Murphy, J. V. (1962) Ca ion uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation, J. Biol. Chem., 237, 2670–2677.PubMedGoogle Scholar
  3. 3.
    Jiang, D., Zhao, L., and Clapham, D. E. (2009) Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter, Science, 326, 144–147, doi: Scholar
  4. 4.
    Palty, R., Silverman, W. F., Hershfinkel, M., Caporale, T., Sensi, S. L., Parnis, J., Nolte, C., Fishman, D., Shoshan-Barmatz, V., Herrmann, S., Khananshvili, D., and Sekler, I. (2010) NCLX is an essential component of mitochon-drial Na+/Ca2+ exchange, Proc. Natl. Acad. Sci. USA, 107, 436–441, doi: Scholar
  5. 5.
    Perocchi, F., Gohil, V. M., Girgis, H. S., Bao, X. R., McCombs, J. E., Palmer, A. E., and Mootha, V. K. (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake, Nature, 467, 291–296, doi: Scholar
  6. 6.
    De Stefani, D., Raffaello, A., Teardo, E., Szabo, I., and Rizzuto, R. (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter, Nature, 476, 336–340, doi: Scholar
  7. 7.
    Baughman, J. M., Perocchi, F., Girgis, H. S., Plovanich, M., Belcher-Timme, C. A., Sancak, Y., Bao, X. R., Strittmatter, L., Goldberger, O., Bogorad, R. L., Koteliansky, V., and Mootha, V. K. (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter, Nature, 476, 341–345, doi: Scholar
  8. 8.
    Raffaello, A., De Stefani, D., Sabbadin, D., Teardo, E., Merli, G., Picard, A., Checchetto, V., Moro, S., Szabo, I., and Rizzuto, R. (2013) The mitochondrial calcium uni-porter is a multimer that can include a dominant-negative pore-forming subunit, EMBO J., 32, 2362–2376, doi: Scholar
  9. 9.
    Plovanich, M., Bogorad, R. L., Sancak, Y., Kamer, K. J., Strittmatter, L., Li, A. A., Girgis, H. S., Kuchimanchi, S., De Groot, J., Speciner, L., Taneja, N., Oshea, J., Koteliansky, V., and Mootha, V. K. (2013) MICU2, a pa-ralog of MICU1, resides within the mitochondrial uni-porter complex to regulate calcium handling, PLoS One, 8, e55785, doi: Scholar
  10. 10.
    Mallilankaraman, K., Cardenas, C., Doonan, P. J., Chandramoorthy, H. C., Irrinki, K. M., Golenar, T., Csordas, G., Madireddi, P., Yang, J., Muller, M., Miller, R., Kolesar, J. E., Molgo, J., Kaufman, B., Hajnoczky, G., Foskett, J. K., and Madesh, M. (2012) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism, Nat. Cell Biol., 14, 1336–1343, doi: Scholar
  11. 11.
    Sancak, Y., Markhard, A. L., Kitami, T., Kovacs-Bogdan, E., Kame, K. J., Udeshi, N. D., Carr, S. A., Chaudhuri, D., Clapham, D. E., Li, A. A., Calvo, S. E., Goldberger, O., and Mootha, V. K. (2013) EMRE is an essential component of the mitochondrial calcium uniporter complex, Science, 342, 1379–1382, doi: Scholar
  12. 12.
    Hoffman, N. E., Chandramoorthy, H. C., Shanmughapriya, S., Zhang, X. Q., Vallem, S., Doonan, P. J., Malliankaraman, K., Guo, S., Rajan, S., Elrod, J. W., Koch, W. J., Cheung, J. Y., and Madesh, M. (2014) SLC25A23 augments mitochondrial Ca2+ uptake, interacts with MCU, and induces oxidative stress-mediated cell death, Mol. Biol. Cell, 25, 936–947, doi: Scholar
  13. 13.
    Bernardi, P., and Petronilli, V. (1996) The permeability transition pore as a mitochondrial calcium release channel: a critical appraisal, J. Bioenerg. Biomembr., 28, 131–138, doi: Scholar
  14. 14.
    Mironova, G. D., Saris, N.-E. L., Belosludtseva, N. V., Agafonov, A. V., Elantsev, A. B., and Belosludtsev, K. N. (2015) Involvement of palmitate/Ca2+(Sr2+)-induced pores in the cycling of ions across the mitochondrial membrane, Biochim. Biophys. Acta, 1848, 488–495, doi: Scholar
  15. 15.
    Bragadin, M., Pozzan, T., and Azzone, G. (1979) Kinetics of Ca2+ carrier in rat liver mitochondria, Biochemistry, 18, 5972–5978, doi: Scholar
  16. 16.
    Pozzan, T., Bragadin, M., and Azzone, G. F. (1977) Disequilibrium between steady-state Ca2+ accumulation ratio and membrane potential in mitochondria. Pathway and role of Ca2+ efflux, Biochemistry, 16, 5618–5625, doi: Scholar
  17. 17.
    Rizzuto, R., Brini, M., Murgia, M., and Pozzan, T. (1993) Microdomains with high Ca2+ close to IP(3)-sensitive channels that are sensed by neighboring mitochondria, Science, 262, 744–747, doi: Scholar
  18. 18.
    Raturi, A., and Simmen, T. (2013) Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane (MAM), Biochim. Biophys. Acta, 1833, 213–224, doi: Scholar
  19. 19.
    Giorgi, C., Missiroli, S., Patergnani, S., Duszynski, J., Wieckowski, M. R., and Pinton, P. (2015) Mitochondria-associated membranes: composition, molecular mechanisms, and physiopathological implications, Antioxid. Redox. Signal., 22, 995–1019, doi: Scholar
  20. 20.
    Poston, C. N., Krishnan, S. C., and Bazemore-Walker, C. R. (2013) In depth proteomic analysis of mammalian mitochondria-associated membranes (MAM), J. Proteomics, 79, 219–230, doi: Scholar
  21. 21.
    Szabadkai, G., Bianchi, K., Varnai, P., De Stefani, D., Wieckowski, M. R., Cavagna, D., Nagy, A. I., Balla, T., and Rizzuto, R. (2006) Chaperone-mediated coupling of endo-plasmic reticulum and mitochondrial Ca2+ channels, J. Cell Biol., 175, 901–911, doi: Scholar
  22. 22.
    De Brito, O. M., and Scorrano, L. (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria, Nature, 456, 605–610, doi: Scholar
  23. 23.
    Hirabayashi, Y., Kwon, S. K., Paek, H., Pernice, W. M., Paul, M. A., Lee, J., Erfani, P., Raczkowski, A., Petrey, D. S., Pon, L. A., and Polleux, F. (2017) ER-mitochondria tethering by PDZD8 regulates Ca2+ dynamics in mammalian neurons, Science, 358, 623–630, doi: Scholar
  24. 24.
    Chernorudskiy, A. L., and Zito, E. (2017) Regulation of calcium homeostasis by ER redox: a close-up of the ER/mitochondria connection, J. Mol. Biol., 429, 620–632, doi: Scholar
  25. 25.
    Giacomello, M., Drago, I., Bortolozzi, M., Scorzeto, M., Gianelle, A., Pizzo, P., and Pozzan, T. (2010) Ca2+ hot spots on the mitochondrial surface are generated by Ca2+ mobilization from stores, but not by activation of store-operated Ca2+ channels, Mol. Cell, 38, 280–290, doi: Scholar
  26. 26.
    Gunter, T., and Pfeiffer, D. (1990) Mechanisms by which mitochondria transport calcium, Am. J. Physiol., 258, 755–786, doi: Scholar
  27. 27.
    Deryabina, Y. I., Isakova, E. P., and Zvyagilskaya, R. A. (2004) Mitochondrial calcium transport systems: properties, regulation, and taxonomic features, Biochemistry (Moscow), 69, 91–102.CrossRefGoogle Scholar
  28. 28.
    Rossi, C. S., Vasington, F. D., and Carafoli, E. (1973) The effect of ruthenium red on the uptake and release of Ca2+ by mitochondria, Biochem. Biophys. Res. Commun., 50, 846–852.CrossRefPubMedGoogle Scholar
  29. 29.
    De Stefani, D., Rizzuto, R., and Pozzan, T. (2016) Enjoy the trip: calcium in mitochondria back and forth, Annu. Rev. Biochem., 85, 161–192, doi: Scholar
  30. 30.
    Saris, N. E., and Carafoli, E. (2005) A historical review of cellular calcium handling, with emphasis on mitochondria, Biochemistry (Moscow), 70, 187–194.CrossRefGoogle Scholar
  31. 31.
    Mironova, G. D., Sirota, T. V., Pronevich, L. A., Trofimenko, N. V., Mironov, G. P., Grigorjev, P. A., and Kondrashova, M. N. (1982) Isolation and properties of Ca2+-transporting glycoprotein and peptide from beef heart mitochondria, J. Bioenerg. Biomembr., 14, 213–225.CrossRefPubMedGoogle Scholar
  32. 32.
    Saris, N. E., Sirota, T. V., Virtanen, I., Niva, K., Penttila, T., Dolgachova, L. P., and Mironova, G. D. (1993) Inhibition of the mitochondrial calcium uniporter by antibodies against a 40-kDa glycoprotein T, J. Bioenerg. Biomembr., 25, 307–312, doi: Scholar
  33. 33.
    Bick, A. G., Calvo, S. E., and Mootha, V. K. (2012) Evolutionary diversity of the mitochondrial calcium uni-porter, Science, 336, 886, doi: Scholar
  34. 34.
    Baradaran, R., Wang, C., Siliciano, A. F., and Long, S. B. (2018) Cryo-EM structures of fungal and metazoan mito-chondrial calcium uniporters, Nature, 559, 580–584, doi: Scholar
  35. 35.
    Yoo, J., Wu, M., Yin, Y., Herzik, M. A., Lander, G. C., and Lee, S. Y. (2018) Cryo-EM structure of a mitochondrial calcium uniporter, Science, 361, 506–511, doi: Scholar
  36. 36.
    Fan, C., Fan, M., Orlando, B. J., Fastman, N. M., Zhang, J., Xu, Y., Chambers, M. G., Xu, X., Perry, K., Liao, M., and Feng, L. (2018) X-ray and cryo-EM structures of the mitochondrial calcium uniporter, Nature, 559, 575–579, doi: Scholar
  37. 37.
    Oxenoid, K., Dong, Y., Cao, C., Cui, T., Sancak, Y., Markhard, A. L., Grabarek, Z., Kong, L., Liu, Z., Ouyang, B., Cong, Y., Mootha, V. K., and Chou, J. J. (2016) Architecture of the mitochondrial calcium uniporter, Nature, 533, 269–273, doi: Scholar
  38. 38.
    Patron, M., Checchetto, V., Raffaello, A., Teardo, E., Vecellio Reane, D., Mantoan, M., Granatiero, V., Szabo, I., De Stefani, D., and Rizzuto, R. (2014) MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity, Mol. Cell, 53, 726–773, doi: Scholar
  39. 39.
    Yamamoto, T., Yamagoshi, R., Harada, K., Kawano, M., Minami, N., Ido, Y., Kuwahara, K., Fujita, A., Ozono, M., Watanabe, A., Yamada, A., Terada, H., and Shinohara, Y. (2016) Analysis of the structure and function of EMRE in a yeast expression system, Biochim. Biophys. Acta, 1857, 831–839, doi: Scholar
  40. 40.
    Vais, H., Mallilankaraman, K., Mak, D., Hoff, H., Payne, R., Tanis, J. E., and Foskett, J. K. (2016) EMRE is a matrix Ca2+ sensor that governs gatekeeping of the mitochondrial Ca2+ uniporter, Cell Rep., 14, 403–410, doi: Scholar
  41. 41.
    Csordas, G., Golenar, T., Seifert, E. L., Kamer, K. J., Sancak, Y., Perocchi, F., Moffat, C., Weaver, D., de la Fuente Perez, S., Bogorad, R., Koteliansky, V., Adijanto, J., Mootha, V. K., and Hajnoczky, G. (2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter, Cell Metab., 17, 976–987, doi: Scholar
  42. 42.
    Kamer, K. J., Sancak, Y., Fomina, Y., Meisel, J. D., Chaudhuri, D., Grabarek, Z., and Mootha, V. K. (2018) MICU1 imparts the mitochondrial uniporter with the ability to discriminate between Ca2+ and Mn2+, Proc. Natl. Acad. Sci. USA, 115, 7960–7969, doi: Scholar
  43. 43.
    Paillard, M., Csordas, G., Szanda, G., Golenar, T., Debattisti, V., Bartok, A., Wang, N., Moffat, C., Seifert, E. L., Spat, A., and Hajnoczky, G. (2017) Tissue-specific mitochondrial decoding of cytoplasmic Ca2+ signals is controlled by the stoichiometry of MICU1/2 and MCU, Cell Rep., 18, 2291–2300, doi: Scholar
  44. 44.
    Kamer, K. J., Grabarek, Z., and Mootha, V. K. (2017) High-affinity cooperative Ca2+ binding by MICU1-MICU2 serves as an on-off switch for the uniporter, EMBO Rep., 18, 1397–1411, doi: Scholar
  45. 45.
    Payne, R., Hoff, H., Roskowski, A., and Foskett, J. K. (2017) MICU2 restricts spatial crosstalk between InsP3R and MCU channels by regulating threshold and gain of MICU1-mediated inhibition and activation of MCU, Cell Rep., 21, 3141–3154, doi: Scholar
  46. 46.
    Paillard, M., Csordas, G., Huang, K. T., Varnai, P., Joseph, S. K., and Hajnoczky, G. (2018) MICU1 interacts with the D-ring of the MCU pore to control its Ca2+ flux and sensitivity to Ru360, Mol. Cell, 72, 778–785, doi: CrossRefPubMedGoogle Scholar
  47. 47.
    Kroner, H. (1986) Ca2+ ions, an allosteric activator of calcium uptake in rat liver mitochondria, Arch. Biochem. Biophys., 251, 525–535, doi: Scholar
  48. 48.
    Kasparinsky, F. O., and Vinogradov, A. D. (1996) Slow Ca2+-induced inactive/active transition of the energy-dependent Ca2+ transporting system of rat liver mitochondria: clue for Ca2+ influx cooperativity, FEBS Lett., 389, 293–296, doi: Scholar
  49. 49.
    Basso, E., Rigotto, G., Zucchetti, A. E., and Pozzan, T. (2108) Slow activation of fast mitochondrial Ca2+ uptake by cytosolic Ca2+, J. Biol. Chem., 293, 17081–17094, doi: Scholar
  50. 50.
    Patron, M., Granatiero, V., Espino, J., Rizzuto, R., and De Stefani, D. (2019) MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake, Cell Death Differ., 26, 179–195, doi: Scholar
  51. 51.
    Ren, T., Wang, J., Zhang, H., Yuan, P., Zhu, J., Wu, Y., Huang, Q., Guo, X., Zhang, J., Ji, L., Li, J., Zhang, H., Yang, H., and Xing, J. (2018) MCUR1-mediated mito-chondrial calcium signaling facilitates cell survival of hepa-tocellular carcinoma via reactive oxygen species-dependent P53 degradation, Antioxid. Redox Signal., 28, 1120–1136, doi: Scholar
  52. 52.
    Paupe, V., Prudent, J., Dassa, E. P., Rendon, O. Z., and Shoubridge, E. A. (2015) CCDC90A (MCUR1) is a cytochrome c oxidase assembly factor and not a regulator of the mitochondrial calcium uniporter, Cell. Metab., 21, 109–116, doi: Scholar
  53. 53.
    Tomar, D., Dong, Z., Shanmughapriya, S., Koch, D. A., Thomas, T., Hoffman, N. E., Timbalia, S. A., Goldman, S. J., Breves, S. L., Corbally, D. P., Nemani, N., Fairweather, J. P., Cutri, A. R., Zhang, X., Song, J., Jana, F., Huang, J., Barrero, C., Rabinowitz, J. E., Luongo, T. S., Schumacher, S. M., Rockman, M. E., Dietrich, A., Merali, S., Caplan, J., Stathopulos, P., Ahima, R. S., Cheung, J. Y., Houser, S. R., Koch, W. J., Patel, V., Gohil, V. M., Elrod, J. W., Rajan, S., and Madesh, M. (2016) MCUR1 is a scaffold factor for the MCU complex function and promotes mitochondrial bioenergetics, Cell. Rep., 15, 1673–1685, doi: Scholar
  54. 54.
    Sparagna, G. C., Gunter, K. K., Sheu, S. S., and Gunter, T. E. (1995) Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode, J. Biol. Chem., 270, 27510–27515, doi: Scholar
  55. 55.
    Wei, A. C., Liu, T., Winslow, R. L., and O’Rourke, B. (2012) Dynamics of matrix-free Ca2+ in cardiac mitochondria: two components of Ca2+ uptake and role of phosphate buffering, J. Gen. Physiol., 139, 465–478, doi: Scholar
  56. 56.
    Beutner, G., Sharma, V. K., Giovannucci, D. R., Yule, D. I., and Sheu, S. S. (2001) Identification of a ryanodine receptor in rat heart mitochondria, J. Biol. Chem., 276, 21482–21488, doi: Scholar
  57. 57.
    Waldeck-Weiermair, M., Jean-Quartier, C., Rost, R., Khan, M. J., Vishnu, N., Bondarenko, A. I., Imamura, H., Malli, R., and Graier, W. F. (2011) Leucine zipper EF hand-containing transmembrane protein 1 (Letm1) and uncoupling proteins 2 and 3 (UCP2/3) contribute to two distinct mitochondrial Ca2+ uptake pathways, J. Biol. Chem., 286, 28444–28455, doi: Scholar
  58. 58.
    Lin, Q. T., and Stathopulos, P. B. (2019) Molecular mechanisms of leucine zipper EF-hand containing transmem-brane protein-1 function in health and disease, Int. J. Mol. Sci., 20, E286, doi: Scholar
  59. 59.
    Brookes, P. S., Parker, N., Buckingham, J. A., Vidal-Puig, A., Halestrap, A. P., Gunter, T. E., Nicholls, D. G., Bernardi, P., Lemasters, J. J., and Brand, M. D. (2008) UCPs-unlikely calcium porters, Nat. Cell Biol., 10, 1235–1237, doi: Scholar
  60. 60.
    Wingrove, D. E., and Gunter, T. E. (1986) Kinetics of mito-chondrial calcium transport. I. Characteristics of the sodium-independent calcium efflux mechanism of liver mitochondria, J. Biol. Chem., 261, 15159–15165.PubMedGoogle Scholar
  61. 61.
    Wingrove, D. E., and Gunter, T. E. (1986) Kinetics of mito-chondrial 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.PubMedGoogle Scholar
  62. 62.
    Marinelli, F., Almagor, L., Hiller, R., Giladi, M., Khananshvili, D., and Faraldo Gomez, J. D. (2014) Sodium recognition by the Na+/Ca2+ exchanger in the outward-facing conformation, Proc. Natl. Acad. Sci. USA, 111, 5354–5362, doi: Scholar
  63. 63.
    Tsai, M. F., Jiang, D., Zhao, L., Clapham, D., and Miller, C. (2014) Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1, J. Gen. Physiol., 143, 67–73, doi: Scholar
  64. 64.
    Khananshvili, D. (2013) The SLC8 gene family of sodium-calcium exchangers (NCX): structure, function, and regulation in health and disease, Mol. Aspects Med., 34, 220–235, doi: Scholar
  65. 65.
    Palty, R., Ohana, E., Hershfinkel, M., Volokita, M., Elgazar, V., Beharier, O., Silverman, W. F., Argaman, M., and Sekler, I. (2004) Lithium-calcium exchange is mediated by a distinct potassium-independent sodium-calcium exchanger, J. Biol. Chem., 279, 25234–25240, doi: Scholar
  66. 66.
    Zhang, Y. L., and Lipton, P. (1999) Cytosolic Ca2+ changes during in vitro ischemia in rat hippocampal slices: major roles for glutamate and Na+-dependent Ca2+ release from mitochondria, J. Neurosci., 19, 3307–3315, doi: 10.1523/JNEUROSCI.19-09-03307.1999.CrossRefPubMedGoogle Scholar
  67. 67.
    Kim, B., and Matsuoka, S. (2008) Cytoplasmic Na+-dependent modulation of mitochondrial Ca2+ via electro-genic mitochondrial Na+-Ca2+ exchange, J. Physiol. (Lond.), 586, 1683–1697, doi: Scholar
  68. 68.
    Samanta, K., Mirams, G. R., and Parekh, A. B. (2018) Sequential forward and reverse transport of the Na+-Ca2+ exchanger generates Ca2+ oscillations within mitochondria, Nat. Commun., 9, 156, doi: Scholar
  69. 69.
    Palty, R., and Sekler, I. (2012) The mitochondrial Na+/Ca2+ exchanger, Cell Calcium, 52, 9–15, doi: Scholar
  70. 70.
    Liao, J., Li, H., Zeng, W., Sauer, D. B., Belmares, R., and Jiang, Y. (2012) Structural insight into the ion-exchange mechanism of the sodium/calcium exchanger, Science, 335, 686–690, doi: Scholar
  71. 71.
    Liao, J., Marinelli, F., Lee, C., Huang, Y., Faraldo-Gomez, J. D., and Jiang, Y. (2016) Mechanism of extracellular ion exchange and binding-site occlusion in a sodium/calcium exchanger, Nat. Struct. Mol. Biol., 23, 590–599, doi: Scholar
  72. 72.
    Hunter, D., and Haworth, R. (1979) The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms, Arch. Biochem. Biophys., 195, 453–459, doi: Scholar
  73. 73.
    Zoratti, M., and Szabo, I. (1995) Mitochondrial permeability transition, Biochim. Biophys. Acta, 1241, 139–176, doi: Scholar
  74. 74.
    Briston, T., Selwood, D. L., Szabadkai, G., and Duchen, M. R. (2019) Mitochondrial permeability transition: a molecular lesion with multiple drug targets, Trends Pharmacol. Sci., 40, 50–70, doi: Scholar
  75. 75.
    Crompton, M., Ellinger, H., and Costi, A. (1988) Inhibition by cyclosporine A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress, Biochem. J., 255, 357–360.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Shanmughapriya, S., Rajan, S., Hoffman, N. E., Higgins, A. M., Tomar, D., Nemani, N., Hines, K. J., Smith, D. J., Eguchi, A., Vallem, S., Shaikh, F., Cheung, M., Leonard, N. J., Stolakis, R. S., Wolfers, M. P., Ibetti, J., Chuprun, J. K., Jog, N. R., Houser, S. R., Koch, W. J., Elrod, J. W., and Madesh, M. (2015) SPG7 is an essential and conserved component of the mitochondrial permeability transition pore, Mol. Cell, 60, 47–62, doi: Scholar
  77. 77.
    Galat, A. (1993) Peptidylproline cis-trans-isomerases: immunophilins, Eur. J. Biochem., 216, 689–707, doi: Scholar
  78. 78.
    Kokoszka, J., Waymire, K., Levy, S., Sligh, J., Gai, J., Jones, D., MacGregor, G., and Wallace, D. (2004) The ADP/ATP translocator is not essential for the mitochon-drial permeability transition pore, Nature, 427, 461–465, doi: Scholar
  79. 79.
    Leung, A. W., Varanyuwatana, P., and Halestrap, A. P. (2008) The mitochondrial phosphate carrier interacts with cyclophilin D and may play a key role in the permeability transition, J. Biol. Chem., 283, 26312–26323, doi: Scholar
  80. 80.
    Giorgio, V., von Stockum, S., Antoniel, M., Fabbro, D., Petronilli, V., Zoratti, M., Szabo, I., Lippe, G., and Bernardi, P. (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore, Proc. Natl. Acad. Sci. USA, 110, 5887–5892, doi: Scholar
  81. 81.
    Bonora, M., Bononi, A., De Marchi, E., Giorgi, C., Lebiedzinska, M., Marchi, S., Patergnani, S., Rimessi, A., Suski, J. M., Wojtala, A., Wieckowski, M. R., Kroemer, G., Galluzzi, L., and Pinton, P. (2013) Role of the c subunit of the Fo ATP synthase in mitochondrial permeability transition, Cell Cycle, 12, 674–683, doi: Scholar
  82. 82.
    Carraro, M., Giorgio, V., Sileikyte, J., Sartori, G., Forte, M., Lippe, G., Zoratti, M., Szabo, I., and Bernardi, P. (2014) Channel formation by yeast F-ATP synthase and the role of dimerization in the mitochondrial permeability transition, J. Biol. Chem., 289, 15980–15985, doi: Scholar
  83. 83.
    Zhou, W., Marinelli, F., Nief, C., and Faraldo-Gomez, J. D. (2017) Atomistic simulations indicate the c-subunit ring of the F1Fo ATP synthase is not the mitochondrial permeability transition pore, Elife, 6, e23781, doi: Scholar
  84. 84.
    He, J., Ford, H. C., Carroll, J., Ding, S., Fearnley, I. M., and Walker, J. E. (2017) Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase, Proc. Natl. Acad. Sci. USA, 114, 3409–3414, doi: Scholar
  85. 85.
    He, J., Carroll, J., Ding, S., Fearnley, I. M., and Walker, J. E. (2017) Permeability transition in human mitochondria persists in the absence of peripheral stalk subunits of ATP synthase, Proc. Natl. Acad. Sci. USA, 114, 9086–9091, doi: Scholar
  86. 86.
    Campanella, M., Casswell, E., Chong, S., Farah, Z., Wieckowski, M. R., Abramov, A. Y., Tinker, A., and Duchen, M. R. (2008) Regulation of mitochondrial structure and function by the F1Fo-ATPase inhibitor protein, IF1, Cell Metab., 8, 13–25, doi: Scholar
  87. 87.
    Altschuld, R. A., Hohl, C. M., Castillo, L. C., Garleb, A. A., Starling, R. C., and Brierley, G. P. (1992) Cyclosporine inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes, Am. J. Physiol., 262, 1699–1704, doi: Scholar
  88. 88.
    Elrod, J. W., Wong, R., Mishra, S., Vagnozzi, R. J., Sakthievel, B., Goonasekera, S. A., Karch, J., Gabel, S., Farber, J., Force, T., Brown, J. H., Murphy, E., and Molkentin, J. D. (2010) Cyclophilin D controls mitochon-drial pore-dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice, J. Clin. Invest., 120, 3680–3687, doi: Scholar
  89. 89.
    Petronilli, V., Miotto, G., Canton, M., Brini, M., Colonna, R., Bernardi, P., and Di Lisa, F. (1999) Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence, Biophys. J., 76, 725–734, doi: Scholar
  90. 90.
    Ichas, F., Jouaville, L. S., Sidash, S. S., Mazat, J.-P., and Holmuhamedov, E. L. (1994) Mitochondrial calcium spiking: a transduction mechanism based on calcium-induced permeability transition involved in cell calcium signaling, FEBS Lett., 348, 211–215, doi: 10.1016/S0006-3495(99)77239-5 Scholar
  91. 91.
    Evtodienko, Y. V., Teplova, V., Khawaja, J., and Saris, N.-E. L. (1994) The Ca2+-induced permeability transition pore is involved in Ca2+-induced mitochondrial oscillations. A study on permeabilized Ehrlich ascites tumor cells, Cell Calcium, 15, 143–152, doi: Scholar
  92. 92.
    Holmuhamedov, E. L., Teplova, V. V., and Chukhlova, E. A. (1991) Excitability of the inner mitochondrial membrane. II. The reversible Sr2+-induced release of Sr2+ from mitochondria, Biol. Membr. (Moscow), 8, 612–2620.Google Scholar
  93. 93.
    Zoratti, M., Szabo, I., and De Marchi, U. (2005) Mitochondrial permeability transitions: how many doors to the house? Biochim. Biophys. Acta, 1706, 40–252, doi: Scholar
  94. 94.
    Sultan, A., and Sokolove, P. (2001) Palmitic acid opens a novel cyclosporine A-insensitive pore in the inner mito-chondrial membrane, Arch. Biochem. Biophys., 386, 31–21, doi: Scholar
  95. 95.
    Mironova, G. D., Gateau-Roesch, O., Levrat, C., Gritsenko, E., Pavlov, E., Lazareva, A. V., Limarenko, E., Rey, P., Louisot, P., and Saris, N.-E. L. (2001) Palmitic and stearic acids bind Ca2+ with high affinity and form nonspecific channels in black-lipid membranes. Possible relation to Ca2+-activated mitochondrial pores, J. Bioenerg. Biomembr., 33, 319–331, doi: 10.1023/A:1010659323937.CrossRefPubMedGoogle Scholar
  96. 96.
    Agafonov, A., Gritsenko, E., Belosludtsev, K., Kovalev, A., Gateau-Roesch, O., Saris, N.-E. L., and Mironova, G. D. (2003) A permeability transition in liposomes induced by the formation of Ca2+/palmitic acid complexes, Biochim. Biophys. Acta, 1609, 153–160, doi: Scholar
  97. 97.
    Belosludtsev, K. N., Trudovishnikov, A. S., Belosludtseva, N. V., Agafonov, A. V., and Mironova, G. D. (2010) Palmitic acid induces the opening of a Ca2+-dependent pore in the plasma membrane of red blood cells: the possible role of the pore in erythrocyte lysis, J. Membr. Biol., 237, 13–19, doi: Scholar
  98. 98.
    Belosludtsev, K., Saris, N.-E., Andersson, L., Belosludtseva, N., Agafonov, A., Sharma, A., Moshkov, D. A., and Mironova, G. D. (2006) On the mechanism of palmitic acid-induced apoptosis: role of pore induced by palmitic acid and Ca2+ in mitochondria, J. Bioenerg. Biomembr., 38, 113–120, doi: Scholar
  99. 99.
    Belosludtsev, K. N., and Mironova, G. D. (2012) Mitochondrial lipid palmitate/Ca2+-induced pore and its possible role in degradation of nerve cells, Patol. Fiziol. Eksp. Terapiya, 3, 220–232.Google Scholar
  100. 100.
    Antonov, V. F., and Shevchenko, E. V. (1995) Lipid pores and stability of cell membranes, Vestn. RAMN, 10, 48–55.Google Scholar
  101. 101.
    Mironova, G. D., Belosludtsev, K. N., Belosludtseva, N. V., Gritsenko, E. N., Khodorov, B. I., and Saris, N.-E. (2007) Mitochondrial Ca2+ cycle mediated by the palmi-tate-activated cyclosporine A-insensitive pore, J. Bioenerg. Biomembr., 39, 167–174, doi: Scholar
  102. 102.
    Murakami, M., Taketomi, Y., Miki, Y., Sato, H., Hirabayashi, T., and Yamamoto, K. (2011) Recent progress in phospholipase A2 research: from cells to animals to humans, Prog. Lipid Res., 50, 152–192, doi: Scholar
  103. 103.
    Holmstrom, K. M., Pan, X., Liu, J. C., Menazza, S., Liu, J., Nguyen, T. T., Pan, H., Parks, R. J., Anderson, S., Noguchi, A., Springer, D., Murphy, E., and Finkel, T. (2015) Assessment of cardiac function in mice lacking the mitochondrial calcium uniporter, J. Mol. Cell Cardiol., 85, 178–182, doi: Scholar
  104. 104.
    Luongo, T. S., Lambert, J. P., Gross, P., Nwokedi, M., Lombardi, A. A., Shanmughapriya, S., Carpenter, A. C., Kolmetzky, D., Gao, E., van Berlo, J. H., Tsai, E. J., Molkentin, J. D., Chen, X., Madesh, M., Houser, S. R., and Elrod, J. W. (2017) The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability, Nature, 545, 93–97, doi: Scholar
  105. 105.
    Bers, D. M. (2002) Cardiac excitation-contraction coupling, Nature, 415, 198–205, doi: Scholar
  106. 106.
    Tinel, H., Cancela, J. M., Mogami, H., Gerasimenko, J. V., Gerasimenko, O. V., Tepikin, A. V., and Petersen, O. H. (1999) Active mitochondria surrounding the pancreatic acinar granule region prevent spreading of inositol trisphosphate-evoked local cytosolic Ca2+ signals, EMBO J., 18, 4999–5008, doi: Scholar
  107. 107.
    Billups, B., and Forsythe, I. D. (2002) Presynaptic mito-chondrial calcium sequestration influences transmission at mammalian central synapses, J. Neurosci., 22, 5840–5847, doi: 20026597.CrossRefPubMedGoogle Scholar
  108. 108.
    Drago, I., De Stefani, D., Rizzuto, R., and Pozzan, T. (2012) Mitochondrial Ca2+ uptake contributes to buffering cyto-plasmic Ca2+ peaks in cardiomyocytes, Proc. Natl. Acad. Sci. USA, 109, 12986–12991, doi: Scholar
  109. 109.
    Denton, R. M. (2009) Regulation of mitochondrial dehy-drogenases by calcium ions, Biochim. Biophys. Acta, 1787, 1309–1316, doi: Scholar
  110. 110.
    Khodorov, B. (2004) Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurons, Prog. Biophys. Mol. Biol., 86, 279–351, doi: Scholar
  111. 111.
    Bolshakov, A. P., Mikhailova, M. M., Szabadkai, G., Pinelis, V. G., Brustovetsky, N., Rizzuto, R., and Khodorov, B. I. (2008) Measurements of mitochondrial pH in cultured cortical neurons clarify contribution of mitochondrial pore to the mechanism of glutamate-induced delayed Ca2+ deregulation, Cell Calcium, 43, 602–614, doi: Scholar
  112. 112.
    Mironova, G. D., Belosludtsev, K. N., Surin, A. M., Trudovishnikov, A. S., Belosludtseva, N. V., Pinelis, V. G., Krasilnikova, I. A., and Khodorov, B. I. (2012) Mitochondrial lipid pore in the mechanism of glutamate-induced calcium deregulation of brain neurons, Biochem. Moscow Suppl. Ser. A, 6, 45–55, doi: Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  • K. N. Belosludtsev
    • 1
    • 2
    Email author
  • M. V. Dubinin
    • 2
  • N. V. Belosludtseva
    • 1
  • G. D. Mironova
    • 1
  1. 1.Institute of Theoretical and Experimental BiophysicsRussian Academy of SciencesPushchino, Moscow RegionRussia
  2. 2.Mari State UniversityYoshkar-OlaRussia

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