Mitochondrial outer membrane proteins assist bid in bax-mediated lipidic pore formation

Blanca Schafer, Joel Quispe, Vineet Choudhary, Jerry E. Chipuk, Teddy G. Ajero, Han Du, Roger Schneiter, Tomomi Kuwana

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Mitochondrial outer membrane permeabilization (MOMP) is a critical step in apoptosis and is regulated by Bcl-2 family proteins. In vitro systems using cardiolipin-containing liposomes have demonstrated the key features of MOMP induced by Bax and cleaved Bid; however, the nature of the "pores" and how they are formed remain obscure. We found that mitochondrial outer membranes contained very little cardiolipin, far less than that required for liposome permeabilization, despite their responsiveness to Bcl-2 family proteins. Strikingly, the incorporation of isolated mitochondrial outer membrane (MOM) proteins into liposomes lacking cardiolipin conferred responsiveness to cleaved Bid and Bax. Cardiolipin dependence was observed only when permeabilization was induced with cleaved Bid but not with Bid or Bim BH3 peptide or oligomerized Bax. Therefore, we conclude that MOM proteins specifically assist cleaved Bid in Bax-mediated permeabilization. Cryoelectron microscopy of cardiolipin-liposomes revealed that cleaved Bid and Bax produced large round holes with diameters of 25-100 nm, suggestive of lipidic pores. In sum, we propose that activated Bax induces lipidic pore formation and that MOM proteins assist cleaved Bid in this process in the absence of cardiolipin.

Original languageEnglish
Pages (from-to)2276-2285
Number of pages10
JournalMolecular Biology of the Cell
Volume20
Issue number8
DOIs
StatePublished - 15 Apr 2009
Externally publishedYes

Fingerprint

Dive into the research topics of 'Mitochondrial outer membrane proteins assist bid in bax-mediated lipidic pore formation'. Together they form a unique fingerprint.

Cite this