Project Details
Projekt
Role and regulation of subcellular membrane lipid peroxidation in ferroptosis
Applicant
Professor Dr. Tobias Dick
Subject Area
Cell Biology
Biochemistry
Biochemistry
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461705428
Ferroptosis takes place when lipid peroxidation (LPO) destroys the integrity of the plasma membrane. LPO can get out of control because it is propagated by a radical chain reaction. Recent data suggest that LPO chain reactions can get started at different subcellular membranes (including those of mitochondria and lysosomes) and that the endoplasmic reticulum is a major hub of LPO and its intracellular spreading, eventually allowing LPO to reach the plasma membrane. Importantly, the role of different organellar membranes in the steps leading to ferroptosis turns out to be highly context dependent. Increasing evidence suggests that the role of ferroptosis promoting and inhibiting factors can differ substantially, depending on the subcellular localization of LPO. In this project we develop and use chemo- and optogenetic tools that can be targeted to specific subcellular membranes, to generate superoxide radicals and/or singlet oxygen, triggering LPO in a highly localized manner. We use these tools to investigate the role of specific subcellular membrane sites in the process leading to ferroptosis. We aim to identify the intracellular locations that are the most sensitive (and the most resistant) towards LPO propagation and ferroptosis induction. We also aim to define the role of individual ferroptosis inhibiting pathways for different endomembrane locations. This also connects us back to the topic of the first funding period, namely the newly discovered role of hydropersulfides as radical scavengers and inhibitors of LPO and ferroptosis. Given the existence of several alternative pathways of persulfide generation and the localization of key persulfide producing enzymes to mitochondria, we ask how persulfides generated from different sources and subcellular locations differ in providing protection to specific organellar membranes.
DFG Programme
Priority Programmes
