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

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 Details

Journal
Nature Metabolism
Published
2025-09-16
DOI
https://doi.org/10.1038/s42255-025-01352-4
Citations
10
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
15.18
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article

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

David Nittner, Raphaël Rodriguez, Nicola Fattorelli, Peter Vangheluwe et al.
10 citations
Nature Metabolism
Ferroptosis and cancer prognosis
15.18
article

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

David Nittner, Raphaël Rodriguez, Nicola Fattorelli, Peter Vangheluwe, Jean‐Christophe Marine, Bernhard Michalke, Pablo Hernández-Varas, Steven H. L. Verhelst, Tatiana Cañeque, Sanket More, Abril Escamilla‐Ayala, Irwin Davidson, Julie Bonnereau, Chris Van den Haute, Jonathan Coene, Christine Gaillet, Francesca Rizzollo, Tito Calí, Joris Van Asselberghs, Lucia Barazzuol, Vivek Venkataramani, Patrizia Agostinis, Natalia Barbara Lysiak
article en
10 citations

Abstract

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.

Nature MetabolismVol. 7(9)
Centre National de la Recherche Scientifique (FR), University of Padua (IT), University of Antwerp (BE), Inserm (FR), Université Paris Sciences et Lettres (FR), Helmholtz Zentrum München (DE), Institut de génétique et de biologie moléculaire et cellulaire (FR), VIB-KU Leuven Center for Cancer Biology (BE), National Center for Tumor Diseases (DE), VIB-KU Leuven Center for Microbiology (BE), Universitätsklinikum Würzburg (DE), VIB-UAntwerp Center for Molecular Neurology (BE), Neuroelectronics Research Flanders (BE), VIB-KU Leuven Center for Brain & Disease Research (BE), KU Leuven (BE)
Openalex Percentile: Top 1%
Ferroptosis and cancer prognosis
15.18
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