Abstract
We aimed to delineate the molecular structures and mechanisms for apoptotic cytochrome c (Cytc) release upon radiation DNA damage to Molt-4 cells by applying the apoptosis inhibitors of the Bcl-XL BH4 peptide and a VDAC1 inhibitor ruthenium red (RuR). IR-induced DBSs upregulates transcriptionally BH3-only PUMA and Noxa through the ATM-p53 activation and induced apoptosis effectively. RNAi of p53 and Bax effectively inhibited IR-induced apoptosis. Without inhibitors, the above BH3-only proteins activated Bax/Bak (IP studies) to result in Bax/Bak oligomers and Bax (Bak)/VDAC1-hybrid dimer (HD)/monomer (HM) in the cross-linked mitochondria (MT). However, the BH4 and RuR completely inhibited IR-induced apoptosis without affecting Bax/Bak activation and oligomerization. Remarkably, the two inhibitors suppressed the HD formation and Cytc release, suggesting an unanticipated, more important role of the HD than oligomers in the MT for cellular apoptosis induced by IR-induced signaling axis of ATM/p53/selected Bcl-2s.
