Non-canonical BIM-regulated Energy Metabolism Determines Drug-induced Liver Necrosis

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2023 Nov 24

PMID 38001256

Authors

Rebekka Lambrecht

Franziska Rudolf

Anna-Katharina Uckert

Valentina C Sladky

Truong San Phan

Jasmin Jansen

Samara Naim

Thomas Kaufmann

Adrian Keogh

Susanne Kirschnek

Aswin Mangerich

Florian Stengel

Marcel Leist

Andreas Villunger

Thomas Brunner

Affiliations

Soon will be listed here.

Abstract

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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