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Kotschi, S.* ; Jung, A.* ; Willemsen, N.* ; Ofoghi, A.* ; Proneth, B. ; Conrad, M. ; Bartelt, A.

NFE2L1-mediated proteasome function protects from ferroptosis.

Mol. Metab. 57:101436 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
OBJECTIVE: Ferroptosis continues to emerge as a novel modality of cell death with important therapeutic implications for a variety of diseases, most notably cancer and degenerative diseases. While susceptibility, initiation, and execution of ferroptosis have been linked to reprogramming of cellular lipid metabolism, imbalances in iron-redox homeostasis, and aberrant mitochondrial respiration, the detailed mechanisms of ferroptosis are still insufficiently well understood. METHODS AND RESULTS: Here we show that diminished proteasome function is a new mechanistic feature of ferroptosis. The transcription factor nuclear factor erythroid-2, like-1 (NFE2L1) protects from ferroptosis by sustaining proteasomal activity. In cellular systems, loss of NFE2L1 reduced cellular viability after the induction of both chemically and genetically induced ferroptosis, which was linked to the regulation of proteasomal activity under these conditions. Importantly, this was reproduced in a Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) patient-derived cell line carrying mutated glutathione peroxidase-4 (GPX4), a critical regulator of ferroptosis. Also, reduced proteasomal activity was associated with ferroptosis in Gpx4-deficient mice. In a mouse model for genetic Nfe2l1 deficiency, we observed brown adipose tissue (BAT) involution, hyperubiquitination of ferroptosis regulators, including the GPX4 pathway, and other hallmarks of ferroptosis. CONCLUSION: Our data highlight the relevance of the NFE2L1-proteasome pathway in ferroptosis. Manipulation of NFE2L1 activity might enhance ferroptosis-inducing cancer therapies as well as protect from aberrant ferroptosis in neurodegeneration, general metabolism, and beyond.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Ferroptosis ; Gpx4 ; Brown Adipose Tissue ; Lipids ; Proteasome ; Ubiquitin
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Zeitschrift Molecular Metabolism
Quellenangaben Band: 57, Heft: , Seiten: , Artikelnummer: 101436 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Institute of Metabolism and Cell Death (MCD)
Förderungen Horizon 2020
Liaoning Medical University
Ministry of Education and Science of the Russian Federation
Else Kroner-Fresenius-Stiftung
Deutsche Forschungsgemeinschaft
European Research Council
Deutsches Zentrum für Herz-Kreislaufforschung