TY  - JOUR
AU  - Gollowitzer, André
AU  - Pein, Helmut
AU  - Rao, Zhigang
AU  - Waltl, Lorenz
AU  - Bereuter, Leonhard
AU  - Loeser, Konstantin
AU  - Meyer, Tobias
AU  - Jafari, Vajiheh
AU  - Witt, Finja
AU  - Winkler, René
AU  - Su, Fengting
AU  - Große, Silke
AU  - Thürmer, Maria
AU  - Grander, Julia
AU  - Hotze, Madlen
AU  - Harder, Sönke
AU  - Espada, Lilia
AU  - Magnutzki, Alexander
AU  - Gstir, Ronald
AU  - Weinigel, Christina
AU  - Rummler, Silke
AU  - Bonn, Günther
AU  - Pachmayr, Johanna
AU  - Ermolaeva, Maria
AU  - Harayama, Takeshi
AU  - Schlüter, Hartmut
AU  - Kosan, Christian
AU  - Heller, Regine
AU  - Thedieck, Kathrin
AU  - Schmitt, Michael
AU  - Shimizu, Takao
AU  - Popp, Jürgen
AU  - Shindou, Hideo
AU  - Kwiatkowski, Marcel
AU  - Koeberle, Andreas
TI  - Attenuated growth factor signaling during cell death initiation sensitizes membranes towards peroxidation.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-00440
SP  - 1774
PY  - 2025
AB  - 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.
KW  - Signal Transduction
KW  - Humans
KW  - Lipid Peroxidation
KW  - Apoptosis
KW  - Cell Membrane: metabolism
KW  - Sterol Regulatory Element Binding Protein 1: metabolism
KW  - Sterol Regulatory Element Binding Protein 1: genetics
KW  - Proto-Oncogene Proteins c-akt: metabolism
KW  - Phospholipids: metabolism
KW  - Fatty Acids, Unsaturated: metabolism
KW  - Cell Death
KW  - Coenzyme A Ligases: metabolism
KW  - Coenzyme A Ligases: genetics
KW  - Animals
KW  - Phosphatidylinositol 3-Kinases: metabolism
KW  - Oxidation-Reduction
KW  - Oxidative Stress
KW  - Ferroptosis
KW  - Sterol Regulatory Element Binding Protein 1 (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-akt (NLM Chemicals)
KW  - Phospholipids (NLM Chemicals)
KW  - Fatty Acids, Unsaturated (NLM Chemicals)
KW  - Coenzyme A Ligases (NLM Chemicals)
KW  - SREBF1 protein, human (NLM Chemicals)
KW  - Phosphatidylinositol 3-Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40000627
DO  - DOI:10.1038/s41467-025-56711-2
UR  - https://inrepo02.dkfz.de/record/299480
ER  -