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Rizzollo, F.* ; Escamilla-Ayala, A.* ; Fattorelli, N.* ; Lysiak, N.B.* ; More, S.K.* ; Hernández Varas, P.* ; Barazzuol, L.* ; van den Haute, C.* ; Van Asselberghs, J.* ; Nittner, D.* ; Coene, J.* ; Venkataramani, V.* ; Michalke, B. ; Gaillet, C.* ; Cañeque, T.* ; Davidson, I.* ; Verhelst, S.H.L.* ; Vangheluwe, P.* ; Calì, T.* ; Marine, J.C.* ; Rodriguez, R.* ; Bonnereau, J.* ; Agostinis, P.*

BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states.

Nat. Metab. 7, 1851-1870 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Iron sustains cancer cell plasticity, yet it also sensitizes the mesenchymal, drug-tolerant phenotype to ferroptosis. This posits that iron compartmentalization must be tightly regulated. However, the molecular machinery governing organelle Fe(II) compartmentalization remains elusive. Here, we show that BDH2 is a key effector of inter-organelle Fe(II) redistribution and ferroptosis vulnerability during melanoma transition from a melanocytic (MEL) to a mesenchymal-like (MES) phenotype. In MEL cells, BDH2 localizes at the mitochondria-lysosome contacts (MLCs) to generate the siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA), which ferries iron into the mitochondria. Fe(II) transfer by BDH2 supports mitochondrial bioenergetics, which is required to maintain lysosomal acidification and MLC formation. Loss of BDH2 alters lysosomal pH and MLC tethering dynamics, causing lysosomal iron sequestration, which primes MES cells for ferroptosis. Rescuing BDH2 expression, or supplementing 2,5-DHBA, rectifies lysosomal pH and MLCs, protecting MES cells from ferroptosis and enhancing their ability to metastasize. Thus, we unveil a BDH2-dependent mechanism that orchestrates inter-organelle Fe(II) transfer, linking metabolic regulation of lysosomal pH to the ferroptosis vulnerability of the mesenchymal, drug-tolerant cancer cells.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Persister Cancer-cells; Heme Oxygenase-2; Trafficking; Homeostasis; Metastasis; Metabolism; Carcinoma; Overload; Pathway; Trpml1
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Zeitschrift Nature metabolism
Quellenangaben Band: 7, Heft: 9, Seiten: 1851-1870 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit BioGeoChemistry and Analytics (BGC)
POF Topic(s) 30202 - Environmental Health
Forschungsfeld(er) Environmental Sciences
PSP-Element(e) G-504800-002
Förderungen Deutsche Forschungsgemeinschaft (German Research Foundation)
FWO
Stichting tegen Kanker
KU Leuven InterAction consortium
EOS DECODE consortium
EOS MetaNiche consortium
ATLANTIS network
Ministry of University and Research
University degli Studi di Padova
PNRR - CN3 National Center for Gene Therapy and Drugs based on RNA Technology
Flemish Research Foundation (FWO) Heavy Infrastructure
DOI 10.1038/s42255-025-01352-4
WOS ID 001572020900001
Scopus ID 105016490082
PubMed ID 40957995
Erfassungsdatum 2025-10-21
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