BIRD-2, a BH4-domain-targeting peptide of Bcl-2, provokes Bax/Bak-independent cell death in B-cell cancers through mitochondrial Ca2+-dependent mPTP opening

• BIRD-2 is an IP 3 R-derived peptide targeting Bcl-2’s BH4 domain, thereby disrupting R/Bcl-2 complexes. causes caspase-dependent cell death in diffuse large B-cell lymphoma lines. elicits apoptotic independently of the pro-apoptotic Bcl-2-family members Bim, Bax and Bak. BIRD-2-induced relies on mitochondrial Ca 2+ uptake permeability transition pore opening. Anti-apoptotic Bcl-2 critically controls by neutralizing at mitochondria. proteins also act endoplasmic reticulum, main intracellular -storage organelle, where they inhibit receptors (IP R) prevent -signaling events. R channels are targeted domain Bcl-2. Some cancer types rely R-Bcl-2 interaction for survival. We previously developed a cell-permeable, BH4-domain-targeting that can abrogate Bcl-2?s inhibitory action Rs, named receptor disrupter-2 (BIRD-2). This kills several Bcl-2-dependent types, including (DLBCL) chronic lymphocytic leukaemia (CLL) cells, eliciting signalling. However, exact mechanisms which these excessive signals triggered provoke remain elusive. Here, we demonstrate DLBCL although activates caspase 3/7 provokes manner, independent members, Instead, overload rapidly followed opening (mPTP). Inhibiting using Ru265, inhibitor uniporter complex counteracts death. Finally, validated our findings primary CLL patient samples provoked Ru265 counteracted Overall, this work reveals death, occurs via but acts members.