Lambrecht, Rebekka; Rudolf, Franziska; Ückert, Anna-Katharina; Sladky, Valentina C; Phan, Truong San; Jansen, Jasmin; Naim, Samara; Kaufmann, Thomas; Keogh, Adrian; Kirschnek, Susanne; Mangerich, Aswin; Stengel, Florian; Leist, Marcel; Villunger, Andreas; Brunner, Thomas (2024). Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis. Cell death and differentiation, 31(1), pp. 119-131. Nature Publishing Group 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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology 04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery 04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine |
UniBE Contributor: |
Naim, Samara Lauren, Kaufmann, Thomas (B), Keogh, Adrian |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1350-9047 |
Publisher: |
Nature Publishing Group |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
27 Nov 2023 11:20 |
Last Modified: |
12 Jan 2024 00:15 |
Publisher DOI: |
10.1038/s41418-023-01245-7 |
PubMed ID: |
38001256 |
BORIS DOI: |
10.48350/189404 |
URI: |
https://boris.unibe.ch/id/eprint/189404 |
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