Anti-apoptotic Bcl-2 family proteins disassemble ceramide channels

Leah J. Siskind, Laurence Feinstein, Tingxi Yu, Joseph S. Davis, David Jones, Jinna Choi, Jonathan E. Zuckerman, Wenzhi Tan, R. Blake Hill, J. Marie Hardwick, Marco Colombini

Research output: Contribution to journalArticle

Abstract

Early in mitochondria-mediated apoptosis, the mitochondrial outer membrane becomes permeable to proteins that, when released into the cytosol, initiate the execution phase of apoptosis. Proteins in the Bcl-2 family regulate this permeabilization, but the molecular composition of the mitochondrial outer membrane pore is under debate. We reported previously that at physiologically relevant levels, ceramides form stable channels in mitochondrial outer membranes capable of passing the largest proteins known to exit mitochondria during apoptosis (Siskind, L. J., Kolesnick, R. N., and Colombini, M. (2006) Mitochondrion 6, 118-125). Here we show that Bcl-2 proteins are not required for ceramide to form protein-permeable channels in mitochondrial outer membranes. However, both recombinant human Bcl-xL and CED-9, the Caenorhabditis elegans Bcl-2 homologue, disassemble ceramide channels in the mitochondrial outer membranes of isolated mitochondria from rat liver and yeast. Importantly, Bcl-xL and CED-9 disassemble ceramide channels in the defined system of solvent-free planar phospholipid membranes. Thus, ceramide channel disassembly likely results from direct interaction with these anti-apoptotic proteins. Mutants of Bcl-xL act on ceramide channels as expected from their ability to be anti-apoptotic. Thus, ceramide channels may be one mechanism for releasing pro-apoptotic proteins from mitochondria during the induction phase of apoptosis.

Original languageEnglish (US)
Pages (from-to)6622-6630
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number11
DOIs
StatePublished - Mar 14 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Siskind, L. J., Feinstein, L., Yu, T., Davis, J. S., Jones, D., Choi, J., Zuckerman, J. E., Tan, W., Hill, R. B., Hardwick, J. M., & Colombini, M. (2008). Anti-apoptotic Bcl-2 family proteins disassemble ceramide channels. Journal of Biological Chemistry, 283(11), 6622-6630. https://doi.org/10.1074/jbc.M706115200