PXD045034

PXD045034 is an original dataset announced via ProteomeXchange.

Title	Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:59:34.191.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Florian Stengel
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	reagent derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-01 07:48:51	ID requested
1	2024-09-24 05:01:55	announced
⏵ 2	2024-10-22 06:59:35	announced	2024-10-22: Updated project metadata.

10.1038/s41418-023-01245-7;

Lambrecht R, Rudolf F, Ü, ckert AK, Sladky VC, Phan TS, Jansen J, Naim S, Kaufmann T, Keogh A, Kirschnek S, Mangerich A, Stengel F, Leist M, Villunger A, Brunner T, Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis. Cell Death Differ, 31(1):119-131(2024) [pubmed]

submitter keyword: APAP, hepatotoxicity, Paracetamol, necrosis

Florian Stengel
contact affiliation	Department of Biology, University of Konstanz, Universitaetsstrasse 10, 78457 Konstanz
contact email	florian.stengel@uni-konstanz.de
lab head
Florian Stengel
contact affiliation	Universität Konstanz
contact email	florian.stengel@uni-konstanz.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/09/PXD045034

PRIDE project URI

• PRIDE
  1. PXD045034
     1. Label: PRIDE project
     2. Name: Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis