BAX insertion, oligomerization, and outer membrane permeabilization in brain mitochondria: Role of permeability transition and SH-redox regulation

Tatiana Brustovetsky, Tsyregma Li, Youyun Yang, Jiang Ting Zhang, Bruno Antonsson, Nickolay Brustovetsky

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23 Scopus citations

Abstract

BAX cooperates with truncated BID (tBID) and Ca2+ in permeabilizing the outer mitochondrial membrane (OMM) and releasing mitochondrial apoptogenic proteins. The mechanisms of this cooperation are still unclear. Here we show that in isolated brain mitochondria, recombinant BAX readily self-integrates/oligomerizes in the OMM but produces only a minuscule release of cytochrome c, indicating that BAX insertion/oligomerization in the OMM does not always lead to massive OMM permeabilization. Ca2+ in a mitochondrial permeability transition (mPT)-dependent and recombinant tBID in an mPT-independent manner promoted BAX insertion/ oligomerization in the OMM and augmented cytochrome c release. Neither tBID nor Ca2+ induced BAX oligomerization in the solution without mitochondria, suggesting that BAX oligomerization required interaction with the organelles and followed rather than preceded BAX insertion in the OMM. Recombinant Bcl-xL failed to prevent BAX insertion/oligomerization in the OMM but strongly attenuated cytochrome c release. On the other hand, a reducing agent, dithiothreitol (DTT), inhibited BAX insertion/oligomerization augmented by tBID or Ca2+ and suppressed the BAX-mediated release of cytochrome c and Smac/DIABLO but failed to inhibit Ca2+-induced swelling. Altogether, these data suggest that in brain mitochondria, BAX insertion/oligomerization can be dissociated from OMM permeabilization and that tBID and Ca2+ stimulate BAX insertion/oligomerization and BAX-mediated OMM permeabilization by different mechanisms involving mPT induction and modulation of the SH-redox state.

Original languageEnglish (US)
Pages (from-to)1795-1806
Number of pages12
JournalBiochimica et Biophysica Acta - Bioenergetics
Volume1797
Issue number11
DOIs
StatePublished - Nov 1 2010

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Keywords

  • BAX
  • Bcl-xL
  • BID
  • Calcium
  • Mitochondria
  • Permeability transition

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology

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