B06: Morrison

Ferroptosis and apoptosis are molecularly controlled cell death modalities. While generally thought to be independent processes, we observed that cell death susceptibilities in response to ferroptotic stress can be modulated by interfering with apoptosis regulation through the use of BH3 mimetics. More precisely, inhibiting anti-apoptotic BCL-2 family proteins such as BCL-2, BCL-x_L or MCL-1 alters cellular outcomes upon ferroptotic stress by GPX4 inhibition or depletion. Surprisingly, this can result in either synergistic cell death or, counter-intuitively, also in cell death suppression. These results thus point towards a complex context-dependent regulation of cell fate decisions at the nexus of apoptosis, ferroptosis and survival. In two coupled and interdisciplinary research strands, both supported through close interactions with further CRC members, we will therefore aim to obtain mechanistic and functional insight into how the compound class of BH3 mimetics can either enhance cell death and synergistically re-route ferroptosis into apoptosis outcomes or suppress ferroptotic cell death and instead promote cell recovery and survival. This will be achieved by quantitatively and kinetically studying how ferroptotic and apoptotic cell death modalities are coupled, both at population and single-cell level, and how survival outcomes are positioned within the landscape of ferroptosis and apoptosis decisions. The research strands planned in this work build on an interdisciplinary and collaborative approach making use of cell biological, biochemical, biophysical and systems biological methodology and will converge to provide us with a holistic understanding and unprecedented insight into the control of cell fate decisions between ferroptosis, apoptosis and survival. Consequently, it will also allow us to define case-specifically optimized interventions to convert cell fates between these outcomes, which could provide perspectives for future therapeutic applications.

Publications

• Boccellato C, Rehm M. TRAIL-induced apoptosis and proteasomal activity - Mechanisms, signalling and interplay. Biochim Biophys Acta Mol Cell Res. 2024 Feb 16;1871(4):119688. doi: 10.1016/j.bbamcr.2024.119688. Epub ahead of print. PMID: 38368955.