The Voltage-dependent Anion Channel Is the Target for a New Class of Inhibitors of the Mitochondrial Permeability Transition Pore

Andrea M. Cesura, Emmanuel Pinard, Robert Schubenel, Valerie Goetschy, Arno Friedlein, Hanno Langen, Peter Polcic, Michael A. Forte, Paolo Bernardi, John A. Kemp

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Abstract

The relevance of the mitochondrial permeability transition pore (PTP) in Ca2+ homeostasis and cell death has gained wide attention. Yet, despite detailed functional characterization, the structure of this channel remains elusive. Here we report on a new class of inhibitors of the PTP and on the identification of their molecular target. The most potent among the compounds prepared, Ro 68-3400, inhibited PTP with a potency comparable to that of cyclosporin A. Since Ro 68-3400 has a reactive moiety capable of covalent modification of proteins, [3H]Ro 68-3400 was used as an affinity label for the identification of its protein target. In intact mitochondria isolated from rodent brain and liver and in SH-SY5Y human neuroblastoma cells, [3H]Ro 68-3400 predominantly labeled a protein of ∼32 kDa. This protein was identified as the isoform 1 of the voltage-dependent anion channel (VDAC). Both functional and affinity labeling experiments indicated that VDAC might correspond to the site for the PTP inhibitor ubiquinone0, whereas other known PTP modulators acted at distinct sites. While Ro 68-3400 represents a new useful tool for the study of the structure and function of VDAC and the PTP, the results obtained provide direct evidence that VDAC1 is a component of this mitochondrial pore.

Original languageEnglish (US)
Pages (from-to)49812-49818
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number50
DOIs
StatePublished - Dec 12 2003

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cesura, A. M., Pinard, E., Schubenel, R., Goetschy, V., Friedlein, A., Langen, H., Polcic, P., Forte, M. A., Bernardi, P., & Kemp, J. A. (2003). The Voltage-dependent Anion Channel Is the Target for a New Class of Inhibitors of the Mitochondrial Permeability Transition Pore. Journal of Biological Chemistry, 278(50), 49812-49818. https://doi.org/10.1074/jbc.M304748200