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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Nature metabolism
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/40957995/ |
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Table of Contents:
- BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states. Rizzollo, Francesca Escamilla-Ayala, Abril Fattorelli, Nicola Lysiak, Natalia Barbara More, Sanket Hernández Varas, Pablo Barazzuol, Lucia Van den Haute, Chris Van Asselberghs, Joris Nittner, David Coene, Jonathan Venkataramani, Vivek Michalke, Bernhard Gaillet, Christine Cañeque, Tatiana Davidson, Irwin Verhelst, Steven H L Vangheluwe, Peter Calì, Tito Marine, Jean-Christophe Rodriguez, Raphaël Bonnereau, Julie Agostinis, Patrizia Ferroptosis Lysosomes Melanoma Iron Mitochondria Humans Cell Line, Tumor Hydrogen-Ion Concentration Animals 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.