MAC inhibitors antagonize the pro-apoptotic effects of tBid and disassemble Bax / Bak oligomers

Pablo M. Peixoto, Oscar Teijido, Oygul Mirzalieva, Laurent M. Dejean, Evgeny Pavlov, Bruno Antonsson, Kathleen W. Kinnally

Research output: Contribution to journalArticle

Abstract

Mitochondrial Apoptotic Channel inhibitors or iMACs are di-bromocarbazole derivatives with anti-apoptotic function which have been tested and validated in several mouse models of brain injury and neurodegeneration. Owing to the increased therapeutic potential of these compounds, we sought to expand our knowledge of their mechanism of action. We investigated the kinetics of MAC inhibition in mitochondria from wild type, Bak, and Bax knockout cell lines using patch clamp electrophysiology, fluorescence microscopy, ELISA, and semiquantitative western blot analyses. Our results show that iMACs work through at least two mechanisms: 1) by blocking relocation of the cytoplasmic Bax protein to mitochondria and 2) by disassembling Bax and Bak oligomers in the mitochondrial outer membrane. iMACs exert comparable effects on channel conductance of Bax or Bak and similarly affect cytochrome c release from Bax or Bak-containing mitochondria. Interestingly, wild type mitochondria were more susceptible to inhibition than the Bak or Bax knockouts. Western blot analysis showed that wild type mitochondria had lower steady state levels of Bak in the absence of apoptotic stimulation.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalJournal of Bioenergetics and Biomembranes
DOIs
StateAccepted/In press - Dec 23 2015

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Mitochondria
Western Blotting
bcl-2-Associated X Protein
Electrophysiology
Mitochondrial Membranes
Cytochromes c
Fluorescence Microscopy
Brain Injuries
Enzyme-Linked Immunosorbent Assay
Cell Line
Therapeutics

Keywords

  • Apoptosis
  • Bak
  • Bax
  • MAC inhibitors
  • MOMP
  • Patch clamp
  • tBid

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

MAC inhibitors antagonize the pro-apoptotic effects of tBid and disassemble Bax / Bak oligomers. / Peixoto, Pablo M.; Teijido, Oscar; Mirzalieva, Oygul; Dejean, Laurent M.; Pavlov, Evgeny; Antonsson, Bruno; Kinnally, Kathleen W.

In: Journal of Bioenergetics and Biomembranes, 23.12.2015, p. 1-10.

Research output: Contribution to journalArticle

Peixoto, Pablo M. ; Teijido, Oscar ; Mirzalieva, Oygul ; Dejean, Laurent M. ; Pavlov, Evgeny ; Antonsson, Bruno ; Kinnally, Kathleen W. / MAC inhibitors antagonize the pro-apoptotic effects of tBid and disassemble Bax / Bak oligomers. In: Journal of Bioenergetics and Biomembranes. 2015 ; pp. 1-10.
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AU - Antonsson, Bruno

AU - Kinnally, Kathleen W.

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