Journal of Bioenergetics and Biomembranes

, Volume 37, Issue 4, pp 237–247 | Cite as

Diacylglycerols Activate Mitochondrial Cationic Channel(s) and Release Sequestered Ca2+

  • Christos Chinopoulos
  • Anatoly A. Starkov
  • Sergey Grigoriev
  • Laurent M. Dejean
  • Kathleen W. Kinnally
  • Xibao Liu
  • Indu S. Ambudkar
  • Gary Fiskum


Mitochondria contribute to cytosolic Ca2+ homeostasis through several uptake and release pathways. Here we report that 1,2-sn-diacylglycerols (DAGs) induce Ca2+ release from Ca2+-loaded mammalian mitochondria. Release is not mediated by the uniporter or the Na+/Ca2+ exchanger, nor is it attributed to putative catabolites. DAGs-induced Ca2+ efflux is biphasic. Initial release is rapid and transient, insensitive to permeability transition inhibitors, and not accompanied by mitochondrial swelling. Following initial rapid release of Ca2+ and relatively slow reuptake, a secondary progressive release of Ca2+ occurs, associated with swelling, and mitigated by permeability transition inhibitors. The initial peak of DAGs-induced Ca2+ efflux is abolished by La3+ (1 mM) and potentiated by protein kinase C inhibitors. Phorbol esters, 1,3-diacylglycerols and 1-monoacylglycerols do not induce mitochondrial Ca2+ efflux. Ca2+-loaded mitoplasts devoid of outer mitochondrial membrane also exhibit DAGs-induced Ca2+ release, indicating that this mechanism resides at the inner mitochondrial membrane. Patch clamping brain mitoplasts reveal DAGs-induced slightly cation-selective channel activity that is insensitive to bongkrekic acid and abolished by La3+. The presence of a second messenger-sensitive Ca2+ release mechanism in mitochondria could have an important impact on intracellular Ca2+ homeostasis.


Mitochondria calcium diacylglycerol mitoplast cation channel permeability transition pore protein kinase C transient receptor potential OAG 













Bongkrekic acid

Cys A

Cyclosporin A


Permeability Transition Pore




1,2-Dioleoylglycerol (18:1)


1,2-Didecanoylglycerol (10:0)




1,2-Dioctanoyl-sn-glycerol (8:0)




Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allan, D., Thomas, P., and Michell, R. H. (1978). Nature 276, 289–290.CrossRefPubMedGoogle Scholar
  2. Baines, C. P., Song, C. X., Zheng, Y. T., Wang, G. W., Zhang, J., Wang, O. L., Guo, Y., Bolli, R., Cardwell, E. M., and Ping, P. (2003). Circ. Res. 92, 873–880.CrossRefPubMedGoogle Scholar
  3. Bell, R. M., and Burns, D. J. (1991). J. Biol. Chem. 266, 4661–4664.PubMedGoogle Scholar
  4. Bernardi, P., Paradisi, V., Pozzan, T., and Azzone, G. F. (1984). Biochemistry 23, 1645–1651.CrossRefPubMedGoogle Scholar
  5. Bernardi, P., Vassanelli, S., Veronese, P., Colonna, R., Szabo, I., and Zoratti, M. (1992). J. Biol. Chem. 267, 2934–2939.PubMedGoogle Scholar
  6. Bothmer, J., Markerink, M., and Jolles, J. (1992). Biochem. Biophys. Res. Commun. 187, 1077–1082.CrossRefPubMedGoogle Scholar
  7. Broekemeier, K. M., and Pfeiffer, D. R. (1989). Biochem. Biophys. Res. Commun. 163, 561–566.CrossRefPubMedGoogle Scholar
  8. Brose, N., Betz, A., and Wegmeyer, H. (2004). Curr. Opin. Neurobiol. 14, 328–340.CrossRefPubMedGoogle Scholar
  9. Brose, N., and Rosenmund, C. (2002). J. Cell Sci. 115, 4399–4411.CrossRefPubMedGoogle Scholar
  10. Chen, C. H., and Lehninger, A. L. (1973). Arch. Biochem. Biophys. 157, 183–196.CrossRefPubMedGoogle Scholar
  11. Chinopoulos, C., Starkov, A. A., and Fiskum, G. (2003). J. Biol. Chem. 278, 27382–27389.CrossRefPubMedGoogle Scholar
  12. Clapham, D. E. (2003). Nature 426, 517–524.PubMedGoogle Scholar
  13. Clapham, D. E., Montell, C., Schultz, G., and Julius, D. (2003). Pharmacol. Rev. 55, 591–596.CrossRefPubMedGoogle Scholar
  14. Florin-Christensen, J., Florin-Christensen, M., Delfino, J. M., Stegmann, T., and Rasmussen, H. (1992). J. Biol. Chem. 267, 14783–14789.PubMedGoogle Scholar
  15. Ford, D. A., and Gross, R. W. (1990). J. Biol. Chem. 265, 12280–12286.PubMedGoogle Scholar
  16. Freeman, M., and Mangiapane, E. H. (1989). Biochem. J. 263, 589–595.PubMedGoogle Scholar
  17. Gudermann, T., Hofmann, T., Schnitzler, M., and Dietrich, A. (2004). Novartis Found. Symp. 258, 103–118.PubMedGoogle Scholar
  18. Gunter, T. E., and Pfeiffer, D. R. (1990). Am. J. Physiol. 258, C755–C786.Google Scholar
  19. Guo, L., Pietkiewicz, D., Pavlov, E. V., Grigoriev, S. M., Kasianowicz, J. J., Dejean, L. M., Korsmeyer, S. J., Antonsson, B., and Kinnally, K. W. (2004). Am. J. Physiol. Cell Physiol. 286, C1109–C1117.CrossRefPubMedGoogle Scholar
  20. Hofmann, T., Obukhov, A. G., Schaefer, M., Harteneck, C., Gudermann, T., and Schultz, G. (1999). Nature 397, 259–263.CrossRefPubMedGoogle Scholar
  21. Hunter, D. R., Haworth, R. A., and Southard, J. H. (1976). J. Biol. Chem. 251, 5069–5077.PubMedGoogle Scholar
  22. Irvine, R. F. (2002). Sci. STKE 2002, RE13.Google Scholar
  23. Kazanietz, M. G. (2002). Mol. Pharmacol. 61, 759–767.CrossRefPubMedGoogle Scholar
  24. Kirichok, Y., Krapivinsky, G., and Clapham, D. E. (2004). Nature 427, 360–364.CrossRefPubMedGoogle Scholar
  25. Knox, C. D., Belous, A. E., Pierce, J. M., Wakata, A., Nicoud, I. B., Anderson, C. D., Pinson, C. W., and Chari, R. S. (2004). Am. J. Physiol. Gastrointest. Liver Physiol. 287, G533–G540.CrossRefPubMedGoogle Scholar
  26. Korge, P., Honda, H. M., and Weiss, J. N. (2002). Proc. Natl. Acad. Sci. U.S.A 99, 3312–3317.CrossRefPubMedGoogle Scholar
  27. Lee, C., Fisher, S. K., Agranoff, B. W., and Hajra, A. K. (1991). J. Biol. Chem. 266, 22837–22846.PubMedGoogle Scholar
  28. Leikin, S., Kozlov, M. M., Fuller, N. L., and Rand, R. P. (1996). Biophys. J. 71, 2623–2632.PubMedGoogle Scholar
  29. Li, L., Lorenzo, P. S., Bogi, K., Blumberg, P. M., and Yuspa, S. H. (1999). Mol. Cell Biol. 19, 8547–8558.PubMedGoogle Scholar
  30. Liscovitch, M., Czarny, M., Fiucci, G., Lavie, Y., and Tang, X. (1999). Biochim. Biophys. Acta 1439, 245–263.PubMedGoogle Scholar
  31. Loupatatzis, C., Seitz, G., Schonfeld, P., Lang, F., and Siemen, D. (2002). Cell. Physiol. Biochem. 12, 269–278.CrossRefPubMedGoogle Scholar
  32. Majumder, P. K., Pandey, P., Sun, X., Cheng, K., Datta, R., Saxena, S., Kharbanda, S., and Kufe, D. (2000). J. Biol. Chem. 275, 21793–21796.CrossRefPubMedGoogle Scholar
  33. Matlib, M. A., Zhou, Z., Knight, S., Ahmed, S., Choi, K. M., Krause-Bauer, J., Phillips, R., Altschuld, R., Katsube, Y., Sperelakis, N., and Bers, D. M. (1998). J. Biol. Chem. 273, 10223–10231.CrossRefPubMedGoogle Scholar
  34. Mikoshiba, K., and Hattori, M. (2000). Sci. STKE 2000, E1.Google Scholar
  35. Mosior, M., and Epand, R. M. (1994). J. Biol. Chem. 269, 13798–13805.PubMedGoogle Scholar
  36. Murray, R. K. (2003). Harper’s Illustrated Biochemistry, Lange Medical Books/McGraw-Hill, New York.Google Scholar
  37. Murriel, C. L., Churchill, E., Inagaki, K., Szweda, L. I., and Mochly-Rosen, D. (2004). J. Biol. Chem. 279, 47985–47991.CrossRefPubMedGoogle Scholar
  38. Nachbaur, J., and Vignais, P. M. (1968). Biochem. Biophys. Res. Commun. 33, 315–320.CrossRefPubMedGoogle Scholar
  39. Nilius, B. (2004). Sci. STKE. 2004, e36.Google Scholar
  40. Nishihira, J., and Ishibashi, T. (1986). Lipids 21, 780–785.PubMedGoogle Scholar
  41. Nishizuka, Y. (1992). Science 258, 607–614.Google Scholar
  42. Nishizuka, Y. (1995). FASEB J. 9, 484–496.PubMedGoogle Scholar
  43. Okada, T., Inoue, R., Yamazaki, K., Maeda, A., Kurosaki, T., Yamakuni, T., Tanaka, I., Shimizu, S., Ikenaka, K., Imoto, K., and Mori, Y. (1999). J. Biol. Chem. 274, 27359–27370.CrossRefPubMedGoogle Scholar
  44. Panagia, V., Ou, C., Taira, Y., Dai, J., and Dhalla, N. S. (1991). Biochim. Biophys. Acta 1064, 242–250.PubMedGoogle Scholar
  45. Pastorino, J. G., Tafani, M., Rothman, R. J., Marcinkeviciute, A., Hoek, J. B., Farber, J. L., and Marcineviciute, A. (1999). J. Biol. Chem. 274, 31734–31739.PubMedGoogle Scholar
  46. Penner, R., and Fleig, A. (2004). Sci. STKE 2004, e38.Google Scholar
  47. Putney, J. W. Jr. (1986). Cell Calcium 7, 1–12.CrossRefPubMedGoogle Scholar
  48. Rajdev, S., and Reynolds, I. J. (1993). Neurosci. Lett. 162, 149–152.CrossRefPubMedGoogle Scholar
  49. Rebecchi, M. J., and Pentyala, S. N. (2000). Physiol. Rev. 80, 1291–1335.PubMedGoogle Scholar
  50. Reed, K. C., and Bygrave, F. L. (1974). Biochem. J. 140, 143–155.PubMedGoogle Scholar
  51. Rustenbeck, I., Munster, W., and Lenzen, S. (1996). Biochim. Biophys. Acta 1304, 129–138.PubMedGoogle Scholar
  52. Ruvolo, P. P., Deng, X., Carr, B. K., and May, W. S. (1998). J. Biol. Chem. 273, 25436–25442.CrossRefPubMedGoogle Scholar
  53. Sato, T., O’Rourke, B., and Marban, E. (1998). Circ. Res. 83, 110–114.PubMedGoogle Scholar
  54. Schmidt, B., Wachter, E., Sebald, W., and Neupert, W. (1984). Eur. J. Biochem. 144, 581–588.CrossRefPubMedGoogle Scholar
  55. Schnaitman, C., Erwin, V. G., and Greenawalt, J. W. (1967). J. Cell Biol. 32, 719–735.CrossRefPubMedGoogle Scholar
  56. Starkov, A. A., and Fiskum, G. (2001). Biochem. Biophys. Res. Commun. 281, 645–650.CrossRefPubMedGoogle Scholar
  57. Storz, P., Hausser, A., Link, G., Dedio, J., Ghebrehiwet, B., Pfizenmaier, K., and Johannes, F. J. (2000). J. Biol. Chem. 275, 24601–24607.CrossRefPubMedGoogle Scholar
  58. Sultan, A., and Sokolove, P. M. (2001). Arch. Biochem. Biophys. 386, 52–61.CrossRefPubMedGoogle Scholar
  59. Szule, J. A., Fuller, N. L., and Rand, R. P. (2002). Biophys. J. 83, 977–984.PubMedGoogle Scholar
  60. Vaena de, A. S., Okamoto, Y., and Hannun, Y. A. (2004). J. Biol. Chem. 279, 11537–11545.CrossRefPubMedGoogle Scholar
  61. Venkatachalam, K., van Rossum, D. B., Patterson, R. L., Ma, H. T., and Gill, D. L. (2002). Nat. Cell Biol. 4, E263–E272.CrossRefPubMedGoogle Scholar
  62. Venkatachalam, K., Zheng, F., and Gill, D. L. (2003). J. Biol. Chem. 278, 29031–29040.CrossRefPubMedGoogle Scholar
  63. Wang, X. (2004). Curr. Opin. Plant Biol. 7, 329–336.CrossRefPubMedGoogle Scholar
  64. Watt, S. A., Kular, G., Fleming, I. N., Downes, C. P., and Lucocq, J. M. (2002). Biochem. J. 363, 657–666.CrossRefPubMedGoogle Scholar
  65. Yang, C., and Kazanietz, M. G. (2003). Trends Pharmacol. Sci. 24, 602–608.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Christos Chinopoulos
    • 1
  • Anatoly A. Starkov
    • 2
  • Sergey Grigoriev
    • 3
  • Laurent M. Dejean
    • 3
  • Kathleen W. Kinnally
    • 3
  • Xibao Liu
    • 4
  • Indu S. Ambudkar
    • 4
  • Gary Fiskum
    • 1
    • 5
  1. 1.Department of AnesthesiologyUniversity of MarylandBaltimore
  2. 2.Department of NeurologyWeill Medical College, Cornell UniversityNew York
  3. 3.Division of Basic SciencesNew York University College of DentistryNew York
  4. 4.Secretory Physiology SectionGene Therapy and Therapeutics Branch, NIDCR, National Institutes of HealthBethesda
  5. 5.Department of AnesthesiologyUniversity of Maryland School of MedicineBaltimore

Personalised recommendations