The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes

K. Nicolaij, R.J.M. Timmers, E. Spoelstra, R. Neut, van, J.J. Fok, Y.M. Huigen, A.J. Verkleij, B. Kruijff, de

Research output: Contribution to journalArticleAcademicpeer-review

80 Citations (Scopus)

Abstract

The interaction of adriamycin with cardiolipin in model membranes and in various membrane preparations derived from rat liver mitochondria was studied and the results are analyzed in the light of a possible specific interaction between adriamycin and cardiolipin. It was found that adriamycin binds to cardiolipin-containing model membranes with a fixed stoichiometry of two drug molecules per cardiolipin. Furthermore, the extent of drug complexation by mitochondria and mitoplasts (inner membrane plus matrix) is in reasonable agreement with their cardiolipin content. In contrast, adriamycin-binding curves of inner membrane ghosts and submitochondrial particles reveal considerable association to an additional site, presumably RNA. The evidence for the potential importance of RNA as a target comes from experiments on outer membranes and microsomes which both appear to bind substantial amounts of adriamycin. Removal of the major part of the RNA associated with these fractions by EDTA treatment is accompanied by a dramatic reduction of binding capacity. We propose that endogenous RNA present in mitochondria and mitoplasts is not accessible for adriamycin at low concentrations of the drug due to the presence of an intact lipid barrier. This potential site comes to expression in ghosts and submitochondrial particles, due to the absence of an intact lipid bilayer and due to the inside-out orientation of the limiting membrane, respectively. Electron microscopical studies show that adriamycin induces dramatic changes in mitochondrial morphology, similar to the uncoupler-induced effects described by Knoll and Brdiezka (Biochim. Biophys. Acta 733, 102–110 (1983)). Adriamycin has an uncoupling effect on mitochondrial respiration and oxidative phosphorylation. The concentration dependence of this effect correlates with the adriamycin-binding curve for mitochondria which implies that only bound adriamycin actively inhibits respiration.
Original languageEnglish
Pages (from-to)359-371
Number of pages13
JournalBiochimica et Biophysica Acta, Biomembranes
Volume778
Issue number2
DOIs
Publication statusPublished - 1984

Fingerprint

Cardiolipins
Mitochondrial Membranes
Liver
Doxorubicin
Rats
Membranes
Mitochondria
RNA
Submitochondrial Particles
Respiration
Pharmaceutical Preparations
Lipid bilayers
Liver Mitochondrion
Oxidative Phosphorylation
Lipid Bilayers
Microsomes
Complexation
Edetic Acid
Stoichiometry
Association reactions

Cite this

Nicolaij, K., Timmers, R. J. M., Spoelstra, E., Neut, van, R., Fok, J. J., Huigen, Y. M., ... Kruijff, de, B. (1984). The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes. Biochimica et Biophysica Acta, Biomembranes, 778(2), 359-371. https://doi.org/10.1016/0005-2736(84)90380-8
Nicolaij, K. ; Timmers, R.J.M. ; Spoelstra, E. ; Neut, van, R. ; Fok, J.J. ; Huigen, Y.M. ; Verkleij, A.J. ; Kruijff, de, B. / The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes. In: Biochimica et Biophysica Acta, Biomembranes. 1984 ; Vol. 778, No. 2. pp. 359-371.
@article{ee80bb7a5fc241e5a495833aa1c96f06,
title = "The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes",
abstract = "The interaction of adriamycin with cardiolipin in model membranes and in various membrane preparations derived from rat liver mitochondria was studied and the results are analyzed in the light of a possible specific interaction between adriamycin and cardiolipin. It was found that adriamycin binds to cardiolipin-containing model membranes with a fixed stoichiometry of two drug molecules per cardiolipin. Furthermore, the extent of drug complexation by mitochondria and mitoplasts (inner membrane plus matrix) is in reasonable agreement with their cardiolipin content. In contrast, adriamycin-binding curves of inner membrane ghosts and submitochondrial particles reveal considerable association to an additional site, presumably RNA. The evidence for the potential importance of RNA as a target comes from experiments on outer membranes and microsomes which both appear to bind substantial amounts of adriamycin. Removal of the major part of the RNA associated with these fractions by EDTA treatment is accompanied by a dramatic reduction of binding capacity. We propose that endogenous RNA present in mitochondria and mitoplasts is not accessible for adriamycin at low concentrations of the drug due to the presence of an intact lipid barrier. This potential site comes to expression in ghosts and submitochondrial particles, due to the absence of an intact lipid bilayer and due to the inside-out orientation of the limiting membrane, respectively. Electron microscopical studies show that adriamycin induces dramatic changes in mitochondrial morphology, similar to the uncoupler-induced effects described by Knoll and Brdiezka (Biochim. Biophys. Acta 733, 102–110 (1983)). Adriamycin has an uncoupling effect on mitochondrial respiration and oxidative phosphorylation. The concentration dependence of this effect correlates with the adriamycin-binding curve for mitochondria which implies that only bound adriamycin actively inhibits respiration.",
author = "K. Nicolaij and R.J.M. Timmers and E. Spoelstra and {Neut, van}, R. and J.J. Fok and Y.M. Huigen and A.J. Verkleij and {Kruijff, de}, B.",
year = "1984",
doi = "10.1016/0005-2736(84)90380-8",
language = "English",
volume = "778",
pages = "359--371",
journal = "Biochimica et Biophysica Acta, Biomembranes",
issn = "0005-2736",
publisher = "Elsevier",
number = "2",

}

Nicolaij, K, Timmers, RJM, Spoelstra, E, Neut, van, R, Fok, JJ, Huigen, YM, Verkleij, AJ & Kruijff, de, B 1984, 'The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes', Biochimica et Biophysica Acta, Biomembranes, vol. 778, no. 2, pp. 359-371. https://doi.org/10.1016/0005-2736(84)90380-8

The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes. / Nicolaij, K.; Timmers, R.J.M.; Spoelstra, E.; Neut, van, R.; Fok, J.J.; Huigen, Y.M.; Verkleij, A.J.; Kruijff, de, B.

In: Biochimica et Biophysica Acta, Biomembranes, Vol. 778, No. 2, 1984, p. 359-371.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes

AU - Nicolaij, K.

AU - Timmers, R.J.M.

AU - Spoelstra, E.

AU - Neut, van, R.

AU - Fok, J.J.

AU - Huigen, Y.M.

AU - Verkleij, A.J.

AU - Kruijff, de, B.

PY - 1984

Y1 - 1984

N2 - The interaction of adriamycin with cardiolipin in model membranes and in various membrane preparations derived from rat liver mitochondria was studied and the results are analyzed in the light of a possible specific interaction between adriamycin and cardiolipin. It was found that adriamycin binds to cardiolipin-containing model membranes with a fixed stoichiometry of two drug molecules per cardiolipin. Furthermore, the extent of drug complexation by mitochondria and mitoplasts (inner membrane plus matrix) is in reasonable agreement with their cardiolipin content. In contrast, adriamycin-binding curves of inner membrane ghosts and submitochondrial particles reveal considerable association to an additional site, presumably RNA. The evidence for the potential importance of RNA as a target comes from experiments on outer membranes and microsomes which both appear to bind substantial amounts of adriamycin. Removal of the major part of the RNA associated with these fractions by EDTA treatment is accompanied by a dramatic reduction of binding capacity. We propose that endogenous RNA present in mitochondria and mitoplasts is not accessible for adriamycin at low concentrations of the drug due to the presence of an intact lipid barrier. This potential site comes to expression in ghosts and submitochondrial particles, due to the absence of an intact lipid bilayer and due to the inside-out orientation of the limiting membrane, respectively. Electron microscopical studies show that adriamycin induces dramatic changes in mitochondrial morphology, similar to the uncoupler-induced effects described by Knoll and Brdiezka (Biochim. Biophys. Acta 733, 102–110 (1983)). Adriamycin has an uncoupling effect on mitochondrial respiration and oxidative phosphorylation. The concentration dependence of this effect correlates with the adriamycin-binding curve for mitochondria which implies that only bound adriamycin actively inhibits respiration.

AB - The interaction of adriamycin with cardiolipin in model membranes and in various membrane preparations derived from rat liver mitochondria was studied and the results are analyzed in the light of a possible specific interaction between adriamycin and cardiolipin. It was found that adriamycin binds to cardiolipin-containing model membranes with a fixed stoichiometry of two drug molecules per cardiolipin. Furthermore, the extent of drug complexation by mitochondria and mitoplasts (inner membrane plus matrix) is in reasonable agreement with their cardiolipin content. In contrast, adriamycin-binding curves of inner membrane ghosts and submitochondrial particles reveal considerable association to an additional site, presumably RNA. The evidence for the potential importance of RNA as a target comes from experiments on outer membranes and microsomes which both appear to bind substantial amounts of adriamycin. Removal of the major part of the RNA associated with these fractions by EDTA treatment is accompanied by a dramatic reduction of binding capacity. We propose that endogenous RNA present in mitochondria and mitoplasts is not accessible for adriamycin at low concentrations of the drug due to the presence of an intact lipid barrier. This potential site comes to expression in ghosts and submitochondrial particles, due to the absence of an intact lipid bilayer and due to the inside-out orientation of the limiting membrane, respectively. Electron microscopical studies show that adriamycin induces dramatic changes in mitochondrial morphology, similar to the uncoupler-induced effects described by Knoll and Brdiezka (Biochim. Biophys. Acta 733, 102–110 (1983)). Adriamycin has an uncoupling effect on mitochondrial respiration and oxidative phosphorylation. The concentration dependence of this effect correlates with the adriamycin-binding curve for mitochondria which implies that only bound adriamycin actively inhibits respiration.

U2 - 10.1016/0005-2736(84)90380-8

DO - 10.1016/0005-2736(84)90380-8

M3 - Article

VL - 778

SP - 359

EP - 371

JO - Biochimica et Biophysica Acta, Biomembranes

JF - Biochimica et Biophysica Acta, Biomembranes

SN - 0005-2736

IS - 2

ER -