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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)

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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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Publication type Article: Journal article

Document type Scientific Article

Keywords Persister Cancer-cells; Heme Oxygenase-2; Trafficking; Homeostasis; Metastasis; Metabolism; Carcinoma; Overload; Pathway; Trpml1

ISSN (print) / ISBN 2522-5812

e-ISSN 2522-5812

Journal Nature metabolism

Quellenangaben Volume: 7, Issue: 9, Pages: 1851-1870

Publisher Springer

Publishing Place London

Reviewing status Peer reviewed

Institute(s) Research Unit BioGeoChemistry and Analytics (BGC)

Grants 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