Journal of Bioenergetics and Biomembranes

, Volume 49, Issue 1, pp 65–74 | Cite as

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 V. Pavlov
  • Bruno Antonsson
  • Kathleen W. Kinnally
Article

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.

Keywords

MAC inhibitors Bax Bak tBid Apoptosis MOMP Patch clamp 

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Baruch College and Graduate Center of City University of New York (CUNY)New YorkUSA
  2. 2.Department of ChemistryCalifornia State University of FresnoFresnoUSA
  3. 3.New York University College of DentistryNew YorkUSA
  4. 4.Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaUSA
  5. 5.Merck Serono, Geneva Research CenterGenevaSwitzerland

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