Project Details
Projekt
The wave of death: ferroptosis propagation from single cell death to tissue damage
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 form of regulated necrosis characterized by the iron-dependent accumulation of lipid peroxides in cellular membranes (Dixon et al., 2012). During the first funding period, we characterized the membrane alterations in model membrane systems of lipid oxidation and cells undergoing ferroptosis in connection to membrane permeabilization and cell death. We found that lipid oxidation increases liposome permeability, associated with increased membrane fluidity and lipid domain reorganization. We also found that ferroptotic cells present strong alterations in the biophysical properties of the plasma membrane related to the loss of functionality associated to cell death. Concretely, we observed an increase in immobile membrane regions, accompanied by increased lipid flip-flop and reduced lipid order. Interestingly, we also detected temporal changes in membrane mechanics leading to reduced tension in the permeabilized state. Using a novel optogenetic system for light-controlled ferroptosis induction, we also found that lipid peroxidation and cell death can propagate to nearby untreated cells through their closely apposed plasma membranes, in line with a wave-like pattern of ferroptosis progression observed in cell culture. This is of high interest because ferroptosis has been linked to necrosis spread observed in diseased tissues, although the mechanisms involved remain elusive. Taking advantage of this unique tool, the overarching goal of this proposal is to gain new insight into how ferroptosis propagates between neighboring cells. We will first determine how the oxidative signals and the alterations in biophysical membrane properties are spread to neighboring cells upon optogenetic ferroptosis induction in selected cells. We will also define the role of cell-cell contacts in ferroptosis propagation and explore how they can be exploited for the regulation of ferroptosis spread. Finally, we will study ferroptosis propagation between cells of different type and in 3D tissues, by taking advantage of engineered self- organizing multi-cellular structures, cancer cell spheroids and kidney organoids. The outcomes of this research will shed new light on the molecular mechanisms involved in the intercellular propagation of ferroptosis establishing a mechanistic link between cell-cell contacts and ferroptosis spread across diseased tissues.
DFG Programme
Priority Programmes
