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Yang, J.S.* ; Morris, A.J.* ; Kamizaki, K.* ; Chen, J.* ; Stark, J.* ; Oldham, W.M.* ; Nakamura, T. ; Mishima, E. ; Loscalzo, J.* ; Minami, Y.* ; Conrad, M. ; Henry, W.S.* ; Hsu, V.W.*

ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1.

Cell 188, 2569-2585.e20 (2025)
Postprint DOI PMC
Open Access Green
Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Aldehyde Dehydrogenase 7a1 ; Ferroptosis ; Ferroptosis Suppressor Protein 1 ; Nicotinamide Adenine Dinucleotide Reduced Form; Cell-death; Apoptosis
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Zeitschrift Cell
Quellenangaben Band: 188, Heft: 10, Seiten: 2569-2585.e20 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-506900-001
Förderungen JSPS KAKENHI
Y.M. (JST Moonshot RD)
European Research Council
German Fed-eral Ministry of Education and Research
CRC TRR 353
AHA
EU

Deutsche Forschungsgemeinschaft/DFG
DOI 10.1016/j.cell.2025.03.019
WOS ID 001494695200001
Scopus ID 105004677162
PubMed ID 40233740
Erfassungsdatum 2025-05-10
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