The Mitochondrial Permeabilization Pore

  • Mario Zoratti
  • Ildiko’ Szabo’
  • Vito De Pinto
Part of the NATO ASI Series book series (volume 83)


The inner membrane of liver or heart mitochondria loaded with more than 30–50 nmol. (mg.prot.)-1 of Ca2+ becomes permeable to solutes of molecular weight up to 1.5 KDa. This “permeability transition” (PT) is now known to be due to the operation of an aspecific pore (the “PTP”) with a diameter of at least 2.8 nm (review: Gunter and Pfeiffer, 1990). The discovery of a high affinity inhibitor, Cyclosporin A, (Fournier et al., 1987; Crompton et al., 1988; Broekemeier et al., 1989) and the possibility of a role of the permeability transition in ischemic damage (Broekemeier et al., 1992; Crompton et al., 1992) have attracted renewed attention towards this phenomenon, at about the same time at which patch-clamp was beginning to be used in mitochondrial research.


Voltage Dependence Mitochondrial Permeability Transition Pore Contact Site Heart Mitochondrion Conductance Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anholt, R.R.H., Pedersen, E., DeSouza, B. and Snyder, S.H (1986) The Peripheral-type Benzodiazepine Receptor. Localization to the mitochondrial outer membrane. J. Biol. Chem. 261, 576–583.PubMedGoogle Scholar
  2. Antonenko, Y.N., Kinnally, K.W., Perini, S. and Tedeschi, H. (1991) Selective effects of inhibitors on inner mito chondrial membrane channels. FEBS Lett. 285, 89–93.PubMedCrossRefGoogle Scholar
  3. Benz, R., Kottke, M. and Brdiczka, D. (1990) The cationi cally selective state of the mitochondrial outer membrane pore: a study with intact mitochondria and reconstituted mitochondrial porin. Biochim. Biophys. Acta 1022, 311–318.PubMedCrossRefGoogle Scholar
  4. Bernardi, P., Vassanelli, S., Veronese, P., Colonna, R. Szabo’, I. and Zoratti, M. (1992) Modulation of the Mitochondrial Permeability Transition Pore. Effect of Protons and divalent Cations. J. Biol.Chem. 267, 2934–2939.PubMedGoogle Scholar
  5. Bernardi, P. (1992) Modulation of the Mitochondrial Cyclo sporin A-sensitive Permeability Transition Pore by the Proton Electrochemical Gradient. Evidence that the Pore can be Opened by Membrane Depolarization. J. Biol. Chem. 267, 8834–8839.PubMedGoogle Scholar
  6. Berrier, C. (1992) Doctorate Thesis, Universite’ Paris Sud, Orsay.Google Scholar
  7. Brdiczka, D. (1991) Contact sites between mitochondrial envelope membranes. Structure and function in energy-and protein-transfer. Biochim. Biophys. Acta 1071, 291–312.PubMedGoogle Scholar
  8. Broekemeier, K., Dempsey, M.E. and Pfeiffer, D.R. (1989) Cyclosporin A is a potent inhibitor of the inner membrane permeability transition in liver mitochon dria. J. Biol. Chem. 264, 7826–7830.PubMedGoogle Scholar
  9. Broekemeier, K. M., Carpenter-Deyo, L., Reed, D. J. and Pfeiffer, D.R. (1992) Cyclosporin A protects hepato cytes subjected to high Ca2+ and oxidative stress. FEBS Lett. 304, 192–194.PubMedCrossRefGoogle Scholar
  10. Colombini, M. (1989) Voltage Gating in the Mitochondrial Channel, VDAC. J. Membr. Biol. 111, 103–111.PubMedCrossRefGoogle Scholar
  11. Crompton, M., Ellinger, H. and Costi, A. (1988) Inhibition by cyclosporin A of a Ca2+-dependent pore activated by inorganic phosphate and oxidative stress in heart mitochondria. Biochem. J. 255, 357–360.PubMedGoogle Scholar
  12. Crompton, M., McGuiness, O. and Nazareth, W. (1992) The involvement of cyclosporin A binding proteins in regulating and uncoupling mitochondrial energy trans, duction. Biochim. Biophys. Acta 1101, 214–217.PubMedGoogle Scholar
  13. De Pinto, V., Prezioso, G. and Palmieri, F. (1987) A simple and rapid method for the purification of the mito chondrial porin from mammalian tissues. Biochim. Biophys. Acta 905, 499–502.PubMedCrossRefGoogle Scholar
  14. Fournier, N., Ducet, G. and Crevat, A. (1987) Action of cyclosporine on mitochondrial calcium fluxes. J. Bioenerg. Biomembr. 19, 297–303.PubMedCrossRefGoogle Scholar
  15. Freitag, H., Neupert, W. and Benz, R. (1982) Purification and Characterization of a Pore Protein of the Outer Mitochondrial Membrane from Neurospora crassa. Eur. J. Biochem. 123, 629–636.PubMedCrossRefGoogle Scholar
  16. Gunter, T.E. and Pfeiffer, D.R. (1990) Mechanisms by which mitochondria transport calcium. Am J. Physiol. 258, C755–C786.PubMedGoogle Scholar
  17. Halestrap, A.P. and Davidson, A.M. (1990) Inhibition of Ca2+-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide transloca se. Biochem J. 268, 153–160.PubMedGoogle Scholar
  18. Hunter, D.R., Haworth, R.A. and Southard, J.H. (1976) Relationship between configuration, function and per meability in calcium-treated mitochondria. J. Biol. Chem. 251, 5069–5077.PubMedGoogle Scholar
  19. Hunter, D.R. and Haworth, R.A. (1979) The Ca2+-induced membrane transition in mitochondria. III. Transitional Ca2+ release. Arch. Biochem. Biophys. 195, 468–477.PubMedCrossRefGoogle Scholar
  20. Hunter, D.R. and Haworth, R.A. (1980) Allosteric inhibi tion of the Ca2+-activated hydrophylic channel of the mitochondrial inner membrane by nucleotides. J. Membr. Biol. 54, 231–236.PubMedCrossRefGoogle Scholar
  21. Kinnally, K.W., Campo, M.L. and Tedeschi, H. (1989) Mito chondrial channel activity studied by patch-clamping mitoplasts. J. Bioenerg. Biomembr. 21, 497–506.PubMedCrossRefGoogle Scholar
  22. Langer, S.Z., Arbilla, S., Tan, S., Lloyd, G., George, P. Allen, J. and Wick, A.E. (1990) Selectivity for Omega Receptor Subtypes as a Strategy for the Development of Anxiolytic Drugs. Pharmacopsychiatry 23, 103–107.PubMedCrossRefGoogle Scholar
  23. LeQuoc, K. and LeQuoc, D. (1988) Involvement of the ADP/ATP Carrier in Calcium-Induced Perturbations of the Mito chondrial Inner Membrane Permeability: Importance of the Orientation of the Nucleotide Binding Site. Arch Biochem. Biophys. 265, 249–257.CrossRefGoogle Scholar
  24. Liu, M.Y. and Colombini, M. (1992) A Soluble Mitochondrial Protein Increases the Voltage Dependence of the Mito chondrial Channel, VDAC. J. Bioenerg. Biomembr. 24, 41–46.PubMedCrossRefGoogle Scholar
  25. Mannella, C., Forte, M. and Colombini, M. (1992) Towards the Molecular Structure of the Mitochondrial Channel VDAC. J. Bioenerg. Biomembr. 24, 7–19.PubMedCrossRefGoogle Scholar
  26. Massari, S. and Azzone, G.F. (1972) The equivalent pore radius of intact and damaged mitochondria and the mechanism of active shrinkage. Biochim. Biophys. Acta 283, 23–29.PubMedCrossRefGoogle Scholar
  27. McEnery, M.W., Snowman, A.M., Trifiletti, R.R. and Snyder, S.H. (1992) Isolation of the mitochondrial benzodia zepine receptor: Association with the voltage-depen dent anion channel and the adenine nucleotide carrier. Proc.Natl. Acad.Sci. USA 89, 3170–3174.PubMedCrossRefGoogle Scholar
  28. Moran, O., Sandri, G., Panfili, E., Stuehmer, W. and Sorgato, M.C. (1990) Electrophysiological Characterization of Contact Sites in Brain Mitochondria. J. Biol. Chem. 265, 908–913.PubMedGoogle Scholar
  29. Moran, O., Sciancalepore, M., Sandri, G., Panfili, E., Bassi, R., Ballarin, C. and Sorgato, M.C. (1992) Ionic permeability of the mitochondrial outer membrane. Eur. Biophys. J. 20, 311–319.PubMedCrossRefGoogle Scholar
  30. Novgorodov, S.A., Gudz, T., Kushnareva, Y.E., Zorov, D.B. and Kudrjashov, Y.B. (1990) Effect of the ADP/ATP anti porter conformational state on the suppression of the nonspecific permeability of the inner mitochon drial membrane by cyclosporine A. FEBS Lett. 277, 123–126.PubMedCrossRefGoogle Scholar
  31. Novgorodov, S.A., Gudz, T.I., Kushnareva, Y.E., Eriksson, O. and Leikin, Y.N. (1991) Effects of the membrane po tential upon the Ca2+ — and cumene hydroperoxide-indu ced permeabilization of the inner mitochondrial mem brane. FEBS Lett. 295, 77–80.PubMedCrossRefGoogle Scholar
  32. Novgorodov, S.A., Gudz, T.I., Milgrom, Y.M. and Brierley, G.P (1992) The Permeability Transition in Heart Mitochon dria Is Regulated Synergistically by ADP and Cyclosporin A. J. Biol. Chem. 267, 16274–16282.PubMedGoogle Scholar
  33. Petronilli, V., Szabo’, I. and Zoratti, M. (1989) The inner mitochondrial membrane contains ion-conducting chan nels similar to those found in bacteria. FEBS Lett. 259, 137–143.PubMedCrossRefGoogle Scholar
  34. Schwaiger, M., Herzog, V. and Neupert, W. (1987) Characteri zation of Translocation Contact Sites Involved in the Import of Mitochondrial Proteins. J. Cell Biol. 105, 235–246.PubMedCrossRefGoogle Scholar
  35. Sorgato, M.C., Keller, B.U. and Stuehmer, W. (1987) Patchclamping of the inner mitochondrial membrane reveals a voltage-dependent channel. Nature 330, 498–500.PubMedCrossRefGoogle Scholar
  36. Szabo’, I. and Zoratti, M. (1991) The Giant Channel of the Inner Mitochondrial Membrane Is Inhibited by Cyclosporin A. J. Biol. Chem. 266, 3376–3379.PubMedGoogle Scholar
  37. Szabo’, I. and Zoratti, M. (1992) The Mitochondrial Mega channel is the Permeability Transition Pore. J. Bioenerg. Biomembr. 24, 111–117.PubMedCrossRefGoogle Scholar
  38. Szabo’, I., Bernardi, P. and Zoratti, M. (1992) Modulation of the Mitochondrial Megachannel by Divalent Cations and Protons. J. Biol. Chem. 267, 2940–2946.PubMedGoogle Scholar
  39. Tedeschi, H., Mannella, C.A. and Bowman, C.L. (1987) Patch Clamping the Outer Mitochondrial Membrane. J. Membr. Biol. 97, 21–29.PubMedCrossRefGoogle Scholar
  40. van Venetje, R. and Verkleij, A.J. (1982) Possible role of non-bilayer lipids in the structure of mitochon dria. A freeze-fracture electron microscopy study. Biochim. Biophys. Acts. 692, 397–405.CrossRefGoogle Scholar
  41. Wunder, U.R. and Colombini, M. (1991) Patch Clamping VDAC in Liposomes Containing Whole Mitochondrial Membra nes. J. Membr. Biol. 123, 83–91.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • Mario Zoratti
    • 1
  • Ildiko’ Szabo’
    • 1
  • Vito De Pinto
    • 1
    • 2
  1. 1.Dept. of Biomedical SciencesCNR Unit for the Physiology of MitochondriaPadovaItaly
  2. 2.Dept. of Pharmaco-BiologyCNR Unit for Mitochondria and BioenergeticsBariItaly

Personalised recommendations