PR002065 (Project)

Description:Programs leading to cell death, such as apoptosis, necroptosis, and ferroptosis, involve an oxidative component linked to lipid metabolism that influences membrane homeostasis. Emerging evidence suggests inter-program cross-talk, emphasizing the need for overarching regulatory mechanisms. We show that under specific cytotoxic stress conditions, exogenous or released polyunsaturated fatty acids (PUFAs) are channeled into overall depleting phospholipids that become vulnerable to peroxidation in the presence of associated redox stress. In fibroblasts, this reprogramming results from reduced growth factor receptor tyrosine kinase (RTK) and phosphatidylinositol-3-kinase (PI3K)/Akt signaling, which reduces de novo fatty acid biosynthesis by mechanisms that differ depending on the specific cytotoxic stressors. We conclude that alterations in PUFA metabolism during cytotoxic stress render cells prone to oxidative modifications in phospholipids.