2. Academic Validation
  3. Attenuated growth factor signaling during cell death initiation sensitizes membranes towards peroxidation

Attenuated growth factor signaling during cell death initiation sensitizes membranes towards peroxidation

  • Nat Commun. 2025 Feb 25;16(1):1774. doi: 10.1038/s41467-025-56711-2.
André Gollowitzer # 1,  Helmut Pein # 2,  Zhigang Rao 1,  Lorenz Waltl 1,  Leonhard Bereuter 1 3,  Konstantin Loeser 2,  Tobias Meyer 4 5,  Vajiheh Jafari 2,  Finja Witt 1,  René Winkler 6 7,  Fengting Su 1 3,  Silke Große 8,  Maria Thürmer 2,  Julia Grander 1,  Madlen Hotze 9,  Sönke Harder 10,  Lilia Espada 11,  Alexander Magnutzki 12,  Ronald Gstir 12,  Christina Weinigel 13,  Silke Rummler 13,  Günther Bonn 12,  Johanna Pachmayr 14,  Maria Ermolaeva 11,  Takeshi Harayama 15,  Hartmut Schlüter 10,  Christian Kosan 6,  Regine Heller 8,  Kathrin Thedieck 9 16 17 18 19,  Michael Schmitt 4,  Takao Shimizu 20 21,  Jürgen Popp 4 5,  Hideo Shindou 22 23,  Marcel Kwiatkowski 9,  Andreas Koeberle 24 25 26
Affiliations

Affiliations

  • 1 Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria.
  • 2 Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany.
  • 3 Institute of Pharmaceutical Sciences and Excellence Field BioHealth, University of Graz, Graz, Austria.
  • 4 Institute of Physical Chemistry and Abbe Center of Photonics, Friedrich-Schiller-University Jena, 07743, Jena, Germany.
  • 5 Leibniz Institute of Photonic Technology Jena e.V., Member of Leibniz Health Technology, 07745, Jena, Germany.
  • 6 Department of Biochemistry, Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University Jena, 07745, Jena, Germany.
  • 7 Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916, Badalona, Spain.
  • 8 Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, 07745, Jena, Germany.
  • 9 Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, 6020, Innsbruck, Austria.
  • 10 Institute of Clinical Chemistry and Laboratory Medicine, Section Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
  • 11 Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745, Jena, Germany.
  • 12 ADSI-Austrian Drug Screening Institute, University of Innsbruck, 6020, Innsbruck, Austria.
  • 13 Institute of Transfusion Medicine, University Hospital Jena, 07747, Jena, Germany.
  • 14 Institute of Pharmacy, Paracelsus Medical University, 5020, Salzburg, Austria.
  • 15 Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur - CNRS UMR7275 - Inserm U1323, 06560, Valbonne, France.
  • 16 Department Metabolism, Senescence and Autophagy, Research Center One Health Ruhr, University Alliance Ruhr & University Hospital Essen, University Duisburg-Essen, 45141, Essen, Germany.
  • 17 Freiburg Materials Research Center FMF, Albert-Ludwigs-University of Freiburg, 79104, Freiburg, Germany.
  • 18 Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands.
  • 19 German Cancer Consortium (DKTK), partner site Essen/Duesseldorf, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147, Essen, Germany.
  • 20 Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan.
  • 21 Institute of Microbial Chemistry, Tokyo 141-0021, Japan.
  • 22 Department of Lipid Life Science, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan.
  • 23 Department of Medical Lipid Science, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 24 Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria. andreas.koeberle@uni-graz.at.
  • 25 Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany. andreas.koeberle@uni-graz.at.
  • 26 Institute of Pharmaceutical Sciences and Excellence Field BioHealth, University of Graz, Graz, Austria. andreas.koeberle@uni-graz.at.
  • # Contributed equally.
PMID: 40000627 DOI: 10.1038/s41467-025-56711-2
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.

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