Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis

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Cell Death and Differentiation. Springer. 2024, 31(1), S. 119-131. ISSN 1350-9047. eISSN 1476-5403. Verfügbar unter: doi: 10.1038/s41418-023-01245-7
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Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury. Modulation of glucose levels and deletion of Mitofusins confirmed that severe APAP toxicity occurs only in cells dependent on oxidative phosphorylation. Glycolytic hepatocytes maintained elevated ATP levels and reduced ROS, which enabled lysosomal recycling of damaged mitochondria by mitophagy. The present study highlights how metabolism and bioenergetics affect drug-induced liver toxicity, and identifies BIM as important regulator of glycolysis, mitochondrial respiration, and oxidative stress signaling.

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ISO 690LAMBRECHT, Rebekka, Franziska RUDOLF, Anna-Katharina ÜCKERT, Valentina C. SLADKY, Truong San PHAN, Jasmin JANSEN, Aswin MANGERICH, Florian STENGEL, Marcel LEIST, Thomas BRUNNER, 2024. Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis. In: Cell Death and Differentiation. Springer. 2024, 31(1), S. 119-131. ISSN 1350-9047. eISSN 1476-5403. Verfügbar unter: doi: 10.1038/s41418-023-01245-7
BibTex
@article{Lambrecht2024Nonca-68622,
  year={2024},
  doi={10.1038/s41418-023-01245-7},
  title={Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis},
  number={1},
  volume={31},
  issn={1350-9047},
  journal={Cell Death and Differentiation},
  pages={119--131},
  author={Lambrecht, Rebekka and Rudolf, Franziska and Ückert, Anna-Katharina and Sladky, Valentina C. and Phan, Truong San and Jansen, Jasmin and Mangerich, Aswin and Stengel, Florian and Leist, Marcel and Brunner, Thomas}
}
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