Anti-apoptotic Bcl-2 Family Proteins Disassemble Ceramide Channels. J Biol Chem 2008 Mar 14;283(11):6622-30
Date
01/04/2008Pubmed ID
18171672Pubmed Central ID
PMC2713582DOI
10.1074/jbc.M706115200Scopus ID
2-s2.0-43749120533 (requires institutional sign-in at Scopus site) 109 CitationsAbstract
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-x(L) 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-x L 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-x L 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.
Author List
Siskind LJ, Feinstein L, Yu T, Davis JS, Jones D, Choi J, Zuckerman JE, Tan W, Hill RB, Hardwick JM, Colombini MMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Apoptosis Regulatory Proteins
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Cell Membrane
Ceramides
Humans
Kidney
Male
Mice
Mitochondria, Liver
Models, Biological
Phospholipids
Proto-Oncogene Proteins c-bcl-2
Rats
Rats, Sprague-Dawley
bcl-X Protein
