Project Details
Projekt
Membrane alterations in ferroptosis: from lipid oxidation to pore-formation
Applicant
Professorin Dr. Ana Jesús Garcia Sáez
Subject Area
Cell Biology
Biophysics
Biophysics
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461705271
Ferroptosis is a caspase-independent form of regulated necrosis characterized by the generation of iron-dependent lipid peroxides in cellular membranes. While it is still unknown how lipid peroxidation leads to ferroptotic cell lysis and death, plasma membrane rupture releases pro-inflammatory damage-associated molecular patterns (DAMPs) leading to necroinflammation and activation of the innate immune system. In this context, ferroptosis has been linked to diseases such as ischemia/reperfusion injury, tissue damage and organ demise, neurodegenerative diseases and cancer. Elucidation of the molecular mechanisms governing membrane rupture during ferroptosis is therefore not only of biological, but also of medical relevance.The overarching goal of this project is to understand how lipid peroxidation triggers plasma membrane permeabilization leading to cell death. We previously found that the final step of ferroptosis execution involves the opening of nanopores at the plasma membrane that cause sustained high cytosolic calcium and cell swelling prior to cell death. Building on these results and our expertise on characterizing membrane permeabilization mechanisms in regulated cell death, in the first aim of this proposal we will determine the alterations in the biophysical properties of cellular membranes in ferroptotic cells. We will use advanced microscopy and biophysical tools to examine the changes in their permeability, fluidity and lateral organization, transmembrane asymmetry and mechanical properties. In the second aim, we will identify by lipidomic analysis which peroxidized lipid species and derivatives are generated in subcellular membranes during ferroptotic progression. Finally, in the third aim, we will validate the functional relevance of previously known and newly identified lipid species for ferroptotic death and relate them to the membrane alterations identified in the first aim. The expected outcome of this research will advance our molecular understanding of ferroptosis by establishing a mechanistic link between lipid peroxidation and execution of cell death.
DFG Programme
Priority Programmes
