BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states
Year: 2025
Type: article
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.
Source: Nature Metabolism
Authors: Francesca Rizzollo, Abril Escamilla-Ayala, Nicola Fattorelli, Natalia Barbara Lysiak, Sanket More, Pablo Hernández Varas, Lucia Barazzuol, Chris Van den Haute, Joris Van Asselberghs, David Nittner, Jonathan Coene, Vivek Venkataramani, Bernhard Michalke, Christine Gaillet, Tatiana Cañeque, Irwin Davidson, Steven H. L. Verhelst, Peter Vangheluwe, Tito Calì, Jean-Christophe Marine, Raphaël Rodriguez, Julie Bonnereau, Patrizia Agostinis
Institutions: VIB-KU Leuven Center for Cancer Biology, KU Leuven, VIB-KU Leuven Center for Brain & Disease Research, University of Antwerp, VIB-UAntwerp Center for Molecular Neurology, University of Padua, University of Würzburg, Universitätsklinikum Würzburg, Helmholtz Munich, Centre National de la Recherche Scientifique, Inserm, Université Paris Sciences et Lettres, Institut Curie, Institut de génétique et de biologie moléculaire et cellulaire
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Awards: 3D SUper-Resolution to cryo-Electron MIcroscopy to study nanoscale subcellular dynamics and structure that alter in Neurodegenerative Diseases - 3SURE MIND, The lymph node pre-metastatic niche: role of the iron metabolism in the tumor invasion and on the immune microenvironment, Therapeutic harnessing of iron-dependent cell death in melanoma; the ApolipoproteinE and ferroptosis link, G5676172616, G5773576668, G703244163, Iron homeostasis in melanoma plasticity and ferroptosis: a matter of contact sites?, G874071777
OpenAlex ID: W4414249397