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Nagakannan, P.* ; Islam, M.I.* ; Conrad, M. ; Eftekharpour, E.*

Cathepsin B is an executioner of ferroptosis.

Biochim. Biophys. Acta-Mol. Cell Res. 1868:118928 (2021)
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Ferroptosis is a necrotic form of cell death caused by inactivation of the glutathione system and uncontrolled iron-mediated lipid peroxidation. Increasing evidence implicates ferroptosis in a wide range of diseases from neurotrauma to cancer, highlighting the importance of identifying an executioner system that can be exploited for clinical applications. In this study, using pharmacological and genetic models of ferroptosis, we observed that lysosomal membrane permeabilization and cytoplasmic leakage of cathepsin B unleashes structural and functional changes in mitochondria and promotes a not previously reported cleavage of histone H3. Inhibition of cathepsin-B robustly rescued cellular membrane integrity and chromatin degradation. We show that these protective effects are independent of glutathione peroxidase-4 and are mediated by preventing lysosomal membrane damage. This was further confirmed when cathepsin B knockout primary fibroblasts remained unaffected in response to various ferroptosis inducers. Our work identifies new and yet-unrecognized aspects of ferroptosis and identifies cathepsin B as a mediator of ferroptotic cell death.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Autophagy ; Glutathione ; Gpx4 ; Histone H3 ; Lipid Peroxidation ; Lysosomes; Dependent Anion Channel; Autophagic Cell-death; Histone H3; Lipid-peroxidation; Oxidative Stress; Lysosomes; Aif; Degradation; Glutathione; Proteasome
Language english
Publication Year 2021
Prepublished in Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 0167-4889
e-ISSN 1879-2596
Journal Biochimica et Biophysica Acta - Molecular Cell Research
Quellenangaben Volume: 1868, Issue: 3, Pages: , Article Number: 118928 Supplement: ,
Publisher Elsevier
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506900-001
Grants Wings for Life foundation, Austria
Will-to-Win foundation
DOI 10.1016/j.bbamcr.2020.118928
WOS ID WOS:000608683900009
Scopus ID 85098081475
PubMed ID 33340545
Erfassungsdatum 2021-02-03
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