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Drug-induced oxidative stress actively prevents caspase activation and hepatocyte apoptosis

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2024

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Deutsche Forschungsgemeinschaft (DFG): INST 38/646-1
Deutsche Forschungsgemeinschaft (DFG): INST 38/657-1
Deutsche Forschungsgemeinschaft (DFG): INST 38/646-1

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Cell Death and Disease. Springer. 2024, 15(9), 659. eISSN 2041-4889. Verfügbar unter: doi: 10.1038/s41419-024-06998-8

Zusammenfassung

Cell death is a fundamental process in health and disease. Emerging research shows the existence of numerous distinct cell death modalities with similar and intertwined signaling pathways, but resulting in different cellular outcomes, raising the need to understand the decision-making steps during cell death signaling. Paracetamol (Acetaminophen, APAP)-induced hepatocyte death includes several apoptotic processes but eventually is executed by oncotic necrosis without any caspase activation. Here, we studied this paradoxical form of cell death and revealed that APAP not only fails to activate caspases but also strongly impedes their activation upon classical apoptosis induction, thereby shifting apoptosis to necrosis. While APAP intoxication results in massive drop in mitochondrial respiration, low cellular ATP levels could be excluded as an underlying cause of missing apoptosome formation and caspase activation. In contrast, we identified oxidative stress as a key factor in APAP-induced caspase inhibition. Importantly, caspase inhibition and the associated switch from apoptotic to necrotic cell death was reversible through the administration of antioxidants. Thus, exemplified by APAP-induced cell death, our study stresses that cellular redox status is a critical component in the decision-making between apoptotic and necrotic cell death, as it directly affects caspase activity.

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570 Biowissenschaften, Biologie

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ISO 690LAMBRECHT, Rebekka, Jasmin JANSEN, Franziska RUDOLF, Mohamed EL-MESERY, Sabrina CAPORALI, Ivano AMELIO, Florian STENGEL, Thomas BRUNNER, 2024. Drug-induced oxidative stress actively prevents caspase activation and hepatocyte apoptosis. In: Cell Death and Disease. Springer. 2024, 15(9), 659. eISSN 2041-4889. Verfügbar unter: doi: 10.1038/s41419-024-06998-8
BibTex
@article{Lambrecht2024-09-09Drugi-70777,
  year={2024},
  doi={10.1038/s41419-024-06998-8},
  title={Drug-induced oxidative stress actively prevents caspase activation and hepatocyte apoptosis},
  number={9},
  volume={15},
  journal={Cell Death and Disease},
  author={Lambrecht, Rebekka and Jansen, Jasmin and Rudolf, Franziska and El-Mesery, Mohamed and Caporali, Sabrina and Amelio, Ivano and Stengel, Florian and Brunner, Thomas},
  note={Article Number: 659}
}
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