Bax targets mitochondria by distinct mechanisms before or during apoptotic cell death: a requirement for VDAC2 or Bak for efficient Bax apoptotic function
SB Ma, TN Nguyen, I Tan, R Ninnis, S Iyer, DA Stroud, M Menard, RM Kluck, MT Ryan, G Dewson
Cell Death & Differentiation | NATURE PUBLISHING GROUP | Published : 2014
In non-apoptotic cells, Bak constitutively resides in the mitochondrial outer membrane. In contrast, Bax is in a dynamic equilibrium between the cytosol and mitochondria, and is commonly predominant in the cytosol. In response to an apoptotic stimulus, Bax and Bak change conformation, leading to Bax accumulation at mitochondria and Bak/Bax oligomerization to form a pore in the mitochondrial outer membrane that is responsible for cell death. Using blue native-PAGE to investigate how Bax oligomerizes in the mitochondrial outer membrane, we observed that, like Bak, a proportion of Bax that constitutively resides at mitochondria associates with voltage-dependent anion channel (VDAC)2 prior to an..View full abstract
Awarded by National Health and Medical Research Council of Australia
Awarded by Association for International Cancer Research
We would like to thank Stephanie Fennell for technical assistance, Colin Hockings for the Bid and Bim BH3 peptides, Mark van Delft for the FLAG-VDAC2 construct, Gabriela Brumatti for fetal liver extraction, William Craigen for the Vdac2<SUP>+/+</SUP> (wild-type) and Vdac2<SUP>-/-</SUP> MEFs, Richard Youle for the wild-type, BAK<SUP>-/-</SUP> and BAX<SUP>-/-</SUP> HCT116 lines and Boris Reljic for the anti-human VDAC2 antibody. The work was supported by grants from the National Health and Medical Research Council of Australia (637335), and the Association for International Cancer Research (10-230), and operational infrastructure grants through the Australian Government IRISS and the Victorian State Government OIS.