Journal of Bioenergetics and Biomembranes

, Volume 26, Issue 5, pp 509–517 | Cite as

Recent progress on regulation of the mitochondrial permeability transition pore; a cyclosporin-sensitive pore in the inner mitochondrial membrane

  • Paolo Bernardi
  • Kimberly M. Broekemeier
  • Douglas R. Pfeiffer


The mitochondrial permeability transition pore allows solutes with a m.w. ≲1500 to equilibrate across the inner membrane. A closed pore is favored by cyclosporin A acting at a high-affinity site, which may be the matrix space cylophilin isozyme. Early results obtained with cyclosporin A analogs and metabolites support this hypothesis. Inhibition by cyclosporin does not appear to require inhibition of calcineurin activity; however, it may relate to inhibition of cyclophilin peptide bond isomerase activity. The permeability transition pore is strongly regulated by both the membrane potential (Δψ) and ΔpH components of the mitochondrial protonmotive force. A voltage sensor which is influenced by the disulfide/sulhydryl state of vicinal sulfhydryls is proposed to render pore opening sensitive to Δψ. Early results indicate that this sensor is also responsive to membrane surface potential and/or to surface potential gradients. Histidine residues located on the matrix side of the inner membrane render the pore responsive to ΔpH. The pore is also regulated by several ions and metabolites which act at sites that are interactive. There are many analogies between the systems which regulate the permeability transition pore and the NMDA receptor channel. These suggest structural similarities and that the permeability transition pore belongs to the family of ligand gated ion channels.

Key words

Mitochondrial permeability transition cyclosporin A cyclosporin analogs transmembrane potential membrane surface potential lipid mediators 


  1. Aizenman, E., Lipton, S. A., and Loring, R. H. (1989).Neuron 2 1257–1263.Google Scholar
  2. Beatrice, M. C., Stiers, D. L., and Pfeiffer, D. R. (1982).J. Biol. Chem. 257 7161–7171.Google Scholar
  3. Bernardi, P. (1992).J. Biol. Chem. 267 8334–8339.Google Scholar
  4. Bernardi, P., Vassanelli, S., Veronese, P., Colonna, R., Szabó, I., and Zoratti, M. (1992).J. Biol. Chem. 267 2934–2939.Google Scholar
  5. Bernardi, P., Veronese, P., and Petronilli, V. (1993).J. Biol. Chem. 268 1005–1010.Google Scholar
  6. Broekemeier, K. M. (1990). Ph.D. Thesis, University of Minnesota, Minneapolis.Google Scholar
  7. Broekemeier, K. M., and Pfeiffer, D. R. (1989).Biochem. Biophys. Res. Commun. 163 561–566.Google Scholar
  8. Broekemeier, K. M., Schmid, P. C., Schmid, H. H. O., and Pfeiffer, D. R. (1985).J. Biol. Chem. 260 105–113.Google Scholar
  9. Broekemeier, K. M., Dempsey, M. E., and Pfeiffer, D. R. (1989).J. Biol. Chem. 264 7829–7830.Google Scholar
  10. Broekemeier, K. M., Carpenter-Deyo, L., Reed, D. J., and Pfeiffer, D. R. (1992).FEBS Lett. 304 192–194.Google Scholar
  11. Connern, C. P., and Halestrap, A. P. (1992).Biochem. J. 284 381–385.Google Scholar
  12. Copeland, K. R., and Yatscoff, R. W. (1990).Transpl. Proc. 22 1146–1149.Google Scholar
  13. Crompton, M., Ellinger, H., and Costi, A. (1988).Biochem. J. 255 357–360.Google Scholar
  14. Davidson, A. M., and Halestrap, A. P. (1990).Biochem. J. 268 147–152.Google Scholar
  15. Dierks, T., Salentin, A., Heberger, C., and Kramer, R. (1990a).Biochim. Biophys. Acta 1028 268–280.Google Scholar
  16. Dierks, T., Salentin, A., and Kramer, R. (1990b).Biochim. Biophys. Acta 1028 281–288.Google Scholar
  17. Fournier, N., Ducet, G., and Crevat, A. (1987).J. Bioenerg. Biomembr. 19 297–303.Google Scholar
  18. Galat, A. (1993).Eur. J. Biochem. 216 689–707.Google Scholar
  19. Griffiths, E. J., and Halestrap, A. P. (1991).Biochem. J. 274 611–614.Google Scholar
  20. Griffiths, E. J., and Halestrap, A. P. (1993).J. Mol. Cell. Cardiol. 25 1461–1469.Google Scholar
  21. Gudz, T. I., Novgorodov, S. A., Brierley, G. P., and Pfeiffer, D. R. (1994).Arch. Biochem. Biophys. 311 219–228.Google Scholar
  22. Gunter, T. E., and Pfeiffer, D. R. (1990).Am. J. Physiol. C755–C786.Google Scholar
  23. Halestrap, A. P. (1991).Biochem. J. 278 715–719.Google Scholar
  24. Halestrap, A. P., and Davidson, A. M. (1990).Biochem. J. 268 153–160.Google Scholar
  25. Haworth, R. A., and Hunter, D. R. (1979).Arch. Biochem. Biophys. 195 460–467.Google Scholar
  26. Haworth, R. A., and Hunter, D. R. (1980).Fed. Proc. 39 1707.Google Scholar
  27. Hunter, D. R., and Haworth, R. A. (1979).Arch. Biochem. Biophys. 195 453–459.Google Scholar
  28. Imberti, R., Nieminen, A.-L., Herman, B., and LeMasters, J. J. (1993).J. Pharmacol. Exp. Ther. 265 392–400.Google Scholar
  29. Jung, D. W., and Brierley, G. P. (1984).J. Biol. Chem. 259 6904–6911.Google Scholar
  30. Kasi, M., Kawasaki, T., and Yamamoto, K. (1992).J. Biochem. 112 197–203.Google Scholar
  31. Kinnally, K. W., Zorov, D. B., Antonenko, Y. N., Snyder, S. H., McEnery, M. W., and Tedeschi, H. (1993).Proc. Natl. Acad. Sci. USA 90 1374–1378.Google Scholar
  32. Kronbach, T., Fischer, V., and Meyer, U. A. (1988).Clin. Pharmacol. Ther. 23 630–635.Google Scholar
  33. Lapidus, R., and Sokolove, P.M. (1992).FEBS Lett. 313 314–318.Google Scholar
  34. Lapidus, R., and Sokolove, P. M. (1993).Arch. Biochem. Biophys. 306 246–253.Google Scholar
  35. Lenartowicz, E., Bernardi, P., and Azzone, G. F. (1991).J. Bioenerg. Biomembr. 23 679–688.Google Scholar
  36. LêQuôc, H., and LêQuôc, D. (1988).Arch. Biochem. Biophys. 265 249–257.Google Scholar
  37. McGuinness, O., Yafei, N., Costi, A., and Crompton, M. (1990).Eur. J. Biochem. 194 671–679.Google Scholar
  38. Mitchell, P. (1966).Biol. Rev. 41 445–501.Google Scholar
  39. Nazareth, W., Yafei, N., and Crompton, M. (1991).J. Mol. Cell Cardiol. 23 1351–1354.Google Scholar
  40. Nicolli, A., Petronilli, V., and Bernardi, P. (1993).Biochemistry 32 4461–4465.Google Scholar
  41. Novgorodov, S. A., Gudz, T. I., Milgrom, Y. M., and Brierley, G. P. (1992).J. Biol. Chem. 267 16274–16282.Google Scholar
  42. Palmieri, F., Bisaccia, F., Lacobazzi, V., Indiversi, C., and Zara, V. (1992).Biochim. Biophys. Acta 1101 223–227.Google Scholar
  43. Pastorino, J. G., Snyder, J. W., Serroni, A., Hoek, J. B., and Farber, J. L. (1993).J. Biol. Chem. 268 13791–13798.Google Scholar
  44. Petronilli, V., Cola, C., and Bernardi, P. (1993a).J. Biol. Chem. 268 1011–1016.Google Scholar
  45. Petronilli, V., Cola, C., Massari, S., Colonna, R., and Bernardi, P. (1993b).J. Biol. Chem. 268 21939–21945.Google Scholar
  46. Petronilli, V., Costantini, P., Scorrano, L., Colonna, R., Passamonti, S., and Bernardi, P. (1994a).J. Biol. Chem. 269 16638–16642.Google Scholar
  47. Petronilli, V., Nicolli, A., Costantini, P., Colonna, R., and Bernardi, P. (1994b).Biochim. Biophys. Acta,1187 255–259.Google Scholar
  48. Riley, W. W., Jr., and Pfeiffer, D. R. (1985).J. Biol. Chem. 260 12416–12425.Google Scholar
  49. Robillard, G. T., and Konings, W. N. (1982).Eur. J. Biochem. 127 597–604.Google Scholar
  50. Rottenberg, H., and Marbach, M. (1990a).Biochem. Biophys. Acta 1016 77–86.Google Scholar
  51. Rottenberg, H., and Marbach, M. (1990b).Biochem. Biophys. Acta 1016 87–98.Google Scholar
  52. Scatton, B. (1993).Fundam. Clin. Pharmacol. 7 389–40.Google Scholar
  53. Scherer, B., and Klingenberg, M. (1974).Biochemistry 13 161–170.Google Scholar
  54. Schreiber, S. L. (1991).Science 251 283–287.Google Scholar
  55. Schreier, M. H., Baumann, G., and Zenke, G. (1993).Transpl. Proc. 25 502–507.Google Scholar
  56. Snyder, J. W., Pastorino, J. G., Attie, A. M., and Farber, J. L. (1992).Biochem. Pharmacol. 44 833–835.Google Scholar
  57. Szabó, I., and Zoratti, M. (1993).FEBS Lett. 330 201–205.Google Scholar
  58. Tang, L.-H., and Aizenman, E. (1993).Mol. Pharmacol. 44 473–478.Google Scholar
  59. Toninello, A., Siliprandi, D., and Siliprandi, N. (1983).Biochem. Biophys. Res. Commun. 111 792–797.Google Scholar
  60. Walsh, C. T., Zydowski, L. D., and McKeon, F. D. (1992).J. Biol. Chem. 267 13115–13118.Google Scholar
  61. Wojtczak, L., and Schönfeld, P. (1993).Biochim. Biophys. Acta 1183 41–57.Google Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Paolo Bernardi
    • 2
  • Kimberly M. Broekemeier
    • 1
  • Douglas R. Pfeiffer
    • 1
  1. 1.From the Department of Medical BiochemistryThe Ohio State UniversityColumbus
  2. 2.CNR Mitochondrial Physiology Unit and Department of Biomedical SciencesUniversity of PadovaPadovaItaly

Personalised recommendations