Outer Membrane Lysis Increases Accessibility of Cationic Drugs to the Inner Mitochondrial Membrane

  • Joyce J. Diwan
  • Carmen A. Mannella
  • Teresa Haley
  • R. Bawa
  • Helen H. Yune


The cationic anticancer drugs adriamycin and MGBG, and the polyamine spermidine, inhibit mitochondrial respiration. This inhibitory effect depends on the integrity of the outer mitochondrial membrane. Lysis of the outer membrane enhances inhibitory interactions of the organic cations with the respiratory chain. Addition of digitonin to Iyse the outer membrane also results in an increment of uptake of isotopically labeled spermidine and MGBG, consistent with rapid penetration of the outer membrane barrier. Subsequent to outer membrane lysis, a slower respiration dependent uptake of spermidine and MGBG is seen, which appears to reflect transport across the inner membrane into the mitochondrial matrix. 14C-Iabeled daunomycin, a structural analog of adriamycin, rapidly binds to the mitochondria by a mechanism which includes non-ionic interactions.


Outer Membrane Organic Cation Outer Mitochondrial Membrane Distribution Space Water Space 
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carbonyl cyanide m-chlorophenylhydrazone


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  1. 1.
    Gosalvez, M., Blanco, M., Hunter, J., Miko, M., and Chance, B. (1974) Europ. J. Cancer 10, 567–574CrossRefGoogle Scholar
  2. 2.
    Mailer, K., and Petering, D.H. (1976) Biochem. Pharm. 25, 2085–2089CrossRefGoogle Scholar
  3. 3.
    Muhammed, H., Ramasarma, T., and Kurup, C.K.R. (1982) Biochim. Biophys. Acta 722, 43–50Google Scholar
  4. 4.
    Mannella, C.A., Capolongo, N., and Berkowitz, R. (1986) Biochim. Biophys. Acta 848, 312–316CrossRefGoogle Scholar
  5. 5.
    Pleshkewych, A., Kramer, D.L., Kelly, E., and Porter, C.W. (1980) Cancer Res. 40, 4533–4540Google Scholar
  6. 6.
    Byczkowski, J.Z., Salamon, W., Harlos, J.P., and Porter, C.W. (1981) Biochem. Pharm. 30, 2851–2860CrossRefGoogle Scholar
  7. 7.
    Nikula, P., Ruohola, H., Alhonen-Hongisto, L, and Janne, J. (1985) Biochem. J. 228, 513–516Google Scholar
  8. 8.
    Williams-Ashman, H.G., and Seidenfeld, J. (1986) Biochem. Pharm. 35, 1217–1225CrossRefGoogle Scholar
  9. 9.
    Chaffee, R.R.J., Arine, R.M., Rochelle, R.H., and Walker, C.D. (1978) in: Advances in Polyamine Research (Campbell, R.A., Morris, D.R., Bartos, D., Daves, G.D., and Bartos, F., eds) Vol. 2, pp. 123–128, Raven Press, New YorkGoogle Scholar
  10. 10.
    Byczkowski, J.Z., Zychlinski, L, and Porter, C.W. (1982) Biochem. Pharm. 31, 4045–4053CrossRefGoogle Scholar
  11. 11.
    Pressman, B.C. (1963) J. Biol. Chem. 238, 401–409Google Scholar
  12. 12.
    Warrell, R.P., and Burchenal, J.H. (1983) J. Clin. Oncol. 1, 52–65Google Scholar
  13. 13.
    Diwan, J.J., Yune, H.H., Haley, T., and Mannella, C.A., submitted for publicationGoogle Scholar
  14. 14.
    Diwan, J.J., Mannella, C.A., and Yune, H.H. (1986) Biophys. J. 49, 94aCrossRefGoogle Scholar
  15. 15.
    Harris, E.J., and VanDam, K. (1968) Biochem. J. 106, 759–766Google Scholar
  16. 16.
    Mannella, C.A., and Parsons, D.F. (1977) Biochim. Biophys. Acta 470, 242–250CrossRefGoogle Scholar
  17. 17.
    Neuberger, M., Journet, E.P., Bligny, R., Carde, J.P., and Douce,R. (1982) Arch. Biochem. Biophys. 211, 312–323CrossRefGoogle Scholar
  18. 18.
    Aronson, D.L., and Diwan, J.J. (1981) Biochemistry 20, 7064–7068CrossRefGoogle Scholar
  19. 19.
    Schnaitman, C., and Greenawalt, J.W. (1968) J. Cell Biol. 38, 158–175CrossRefGoogle Scholar
  20. 20.
    Mitchell, P. (1979) Science 206, 1148–1159CrossRefGoogle Scholar
  21. 21.
    Mitchell, P., and Moyle, J. (1969) Eur. J. Biochem. 7, 471–484CrossRefGoogle Scholar
  22. 22.
    Sokolove, P.M. (1984) Biochem. Pharm. 33, 3513–3515CrossRefGoogle Scholar
  23. 23.
    Cheneval, D., Muller, M., Toni, R., Ruetz, S., and Carafoli, E. (1985) J. Biol. Chem. 260, 13003–13007Google Scholar
  24. 24.
    Henry, N., Fantine, E.O., Bolard, J., and Garnier-Suillerot, A. (1985) Biochemistry 24, 7085–7092CrossRefGoogle Scholar
  25. 25.
    Fiallo, M.M.L., and Garnier-Suillerot, A. (1986) Biochim. Biophys. Acta 854, 143–146CrossRefGoogle Scholar
  26. 26.
    Colombini, M. (1979) Nature 279, 643–645CrossRefGoogle Scholar
  27. 27.
    Colombini, M. (1980) J. Membr. Biol. 53, 79–84CrossRefGoogle Scholar
  28. 28.
    Roos, N., Benz, R., and Brdiczka, D. (1982) Biochim. Biophys. Acta 686, 204–214CrossRefGoogle Scholar
  29. 29.
    Freitag, H., Neupert, W., and Benz, R. (1982) Eur. J. Biochem. 123, 629–636CrossRefGoogle Scholar
  30. 30.
    Mannella, C., and Colombini, M. (1984) Biochim. Biophys. Acta 774, 206–214CrossRefGoogle Scholar
  31. 31.
    De Pinto, V., Tommasino, M., Benz, R., and Palmieri F. (1985) Biochim. Biophys. Acta 813, 230–242CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Joyce J. Diwan
    • 1
  • Carmen A. Mannella
    • 1
    • 2
  • Teresa Haley
    • 1
  • R. Bawa
    • 1
  • Helen H. Yune
    • 1
  1. 1.Biology DepartmentRensselaer Polytechnic InstituteTroyUSA
  2. 2.Wadsworth Center for Laboratories and Research State of New York Department of Health, and School of Public Health SciencesState University of New York at AlbanyAlbanyUSA

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