Attenuated growth factor signaling during cell death initiation sensitizes membranes towards peroxidation
Abstract
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.
Article Details
Authors (35)
André Gollowitzer
Helmut Pein
Zhigang Rao
Lorenz Waltl
Leonhard Bereuter
Konstantin Loeser
Tobias Meyer
Vajiheh Jafari
Finja Witt
René Winkler
Fengting Su
Silke Große
Maria Thürmer
Julia Grander
Madlen Hotze
Institute of Biochemistry, Faculty of Chemistry and Pharmacy, University of Innsbruck
Sönke Harder
Lilia Espada
Alexander Magnutzki
Ronald Gstir
Christina Weinigel
Silke Rummler
Günther Bonn
Johanna Pachmayr
Maria Ermolaeva
Takeshi Harayama
Hartmut Schlüter
Christian Kosan
Regine Heller
Kathrin Thedieck
Michael Schmitt
Takao Shimizu
Research Center for Electronic and Optical Materials, National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan
Jürgen Popp
Hideo Shindou
Marcel Kwiatkowski
Institute of Biochemistry, Faculty of Chemistry and Pharmacy, University of Innsbruck
Andreas Koeberle