Apoptotic cell death is governed by the BCL2 protein family, with dysregulated apoptosis contributing to cancer, inflammation, and degenerative diseases. A key step in the apoptotic pathway is the formation of pores by two BCL2 family members BAK and BAX, to initiate mitochondrial outer membrane permeabilisation (MOMP). The mechanism of MOMP remains poorly defined. Unlike several pore-forming proteins, BAK and BAX do not form a tight ring or arc of protein during MOMP, implying that membrane forces rather than a protein-protein interface drive the proteins to cluster and trigger pores. Our preliminary findings indicate that targeting the membrane may provide a novel means of regulating apoptosis and could provide opportunities to enhance anti-cancer treatment.
This project will have two parts. Firstly, advanced microscopy, including FLIM and super-resolution microscopy, will measure membrane changes (disorder, microdomains) during apoptotic pore formation in native membranes. Secondly, lipidomics will be employed to understand the specific lipid features of apoptotic pores in contrast to other types of membrane pores. This project will involve a range of established cell biology and biochemistry techniques in addition to cutting-edge live microscopy approaches and targeted lipidomics.
