ER–mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis

Ferroptosis is a form of regulated cell death characterized by peroxidation of phospholipids (PLs). The following thesis critically reviews a recent article, which investigates how this process starts at endoplasmic reticulum-mitochondria contact sites (EMCSs). In this study, super-resolution live-cell imaging has been used to reconstruct the spatiotemporal dynamics of ferroptosis at the interorganelle level. The authors demonstrated that EMCSs expand rapidly upon initial PL peroxidation and, afterward, oxidative stress propagates to mitochondria, leading to mitochondrial ROS production and fission. Oxidative lipidomic analysis further revealed that EMCSs are enriched in proferroptotic polyunsaturated phospholipids. Functional experiments, performed in murine embryonic fibroblasts and human triple-negative breast cancer cells, showed that disrupting ER-mitochondria tethering reduced PL peroxidation and ferroptosis, whereas stabilizing these contact sites enhanced both processes, suggesting a therapeutic strategy for inducing ferroptosis in cancer cells. In this thesis, the experimental approach, the main findings and the wider implications of this research are evaluated.