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 Große, Maria Thürmer, Julia Grander, Madlen Hotze, 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, Jürgen Popp, Hideo Shindou, Marcel Kwiatkowski and Andreas Koeberle ()
Additional contact information
André Gollowitzer: University of Innsbruck
Helmut Pein: Friedrich-Schiller-University Jena
Zhigang Rao: University of Innsbruck
Lorenz Waltl: University of Innsbruck
Leonhard Bereuter: University of Innsbruck
Konstantin Loeser: Friedrich-Schiller-University Jena
Tobias Meyer: Friedrich-Schiller-University Jena
Vajiheh Jafari: Friedrich-Schiller-University Jena
Finja Witt: University of Innsbruck
René Winkler: Friedrich-Schiller-University Jena
Fengting Su: University of Innsbruck
Silke Große: Jena University Hospital
Maria Thürmer: Friedrich-Schiller-University Jena
Julia Grander: University of Innsbruck
Madlen Hotze: University of Innsbruck
Sönke Harder: University Medical Center Hamburg-Eppendorf
Lilia Espada: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Alexander Magnutzki: University of Innsbruck
Ronald Gstir: University of Innsbruck
Christina Weinigel: University Hospital Jena
Silke Rummler: University Hospital Jena
Günther Bonn: University of Innsbruck
Johanna Pachmayr: Paracelsus Medical University
Maria Ermolaeva: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Takeshi Harayama: Université Côte d’Azur - CNRS UMR7275 - Inserm U1323
Hartmut Schlüter: University Medical Center Hamburg-Eppendorf
Christian Kosan: Friedrich-Schiller-University Jena
Regine Heller: Jena University Hospital
Kathrin Thedieck: University of Innsbruck
Michael Schmitt: Friedrich-Schiller-University Jena
Takao Shimizu: National Center for Global Health and Medicine
Jürgen Popp: Friedrich-Schiller-University Jena
Hideo Shindou: National Center for Global Health and Medicine
Marcel Kwiatkowski: University of Innsbruck
Andreas Koeberle: University of Innsbruck

Nature Communications, 2025, vol. 16, issue 1, 1-31

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.

Date: 2025
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DOI: 10.1038/s41467-025-56711-2

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