Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
01 2024
01 2024
Historique:
received:
16
02
2023
accepted:
14
11
2023
revised:
02
11
2023
medline:
12
1
2024
pubmed:
25
11
2023
entrez:
24
11
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 38001256
doi: 10.1038/s41418-023-01245-7
pii: 10.1038/s41418-023-01245-7
pmc: PMC10781779
doi:
Substances chimiques
Acetaminophen
362O9ITL9D
Bcl-2-Like Protein 11
0
Adenosine Triphosphate
8L70Q75FXE
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
119-131Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : INST 38/657-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : BR 3369/5-2
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : INST 38/646-1
Informations de copyright
© 2023. The Author(s).
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