Attenuated growth factor signaling during cell death initiation sensitizes membranes towards peroxidation
André Gollowitzer, Helmut Pein, Zhigang Rao, Lorenz Waltl, Leonhard Bereuter, Konstantin Loeser, Tobias Meyer, Vajiheh Jafari, Finja Witt, René Winkler, Fengting Su, Silke Größe, Maria Thürmer, Julia Grander, Madlen Hotze, Sönke Harder, Lília Espada, Alexander Magnutzki, Ronald Gstir, Christina Weinigel, Silke Rummler, Günther K. Bonn, Johanna Pachmayr, Maria Ermolaeva, T. HARAYAMA, Hartmut Schlüter, Christian Kosan, Regine Heller, Kathrin Thedieck, Michael Schmitt, Takao Shimizu, Jürgen Popp, Hideo Shindou, Marcel Kwiatkowski, Andreas Koeberle
Abstract
Cell death programs such as apoptosis and ferroptosis are associated with aberrant redox homeostasis linked to lipid metabolism and membrane function. Evidence for cross-talk between these programs is emerging. Here, we show that cytotoxic stress channels polyunsaturated fatty acids via lysophospholipid acyltransferase 12 into phospholipids that become susceptible to peroxidation under additional redox stress. This reprogramming is associated with altered acyl-CoA synthetase isoenzyme expression and caused by a decrease in growth factor receptor tyrosine kinase (RTK)-phosphatidylinositol-3-kinase signaling, resulting in suppressed fatty acid biosynthesis, for specific stressors via impaired Akt-SREBP1 activation. The reduced availability of de novo synthesized fatty acids favors the channeling of polyunsaturated fatty acids into phospholipids. Growth factor withdrawal by serum starvation mimics this phenotype, whereas RTK ligands counteract it. We conclude that attenuated RTK signaling during cell death initiation increases cells' susceptibility to oxidative membrane damage at the interface of apoptosis and alternative cell death programs.