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
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引用次数: 0
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. Rizzollo et al. show that BDH2 participates in iron distribution between cellular compartments, which sets the threshold for the ferroptosis vulnerability of the melanoma cell phenotypes, ultimately affecting their metastatic capacity
期刊介绍:
Nature Metabolism is a peer-reviewed scientific journal that covers a broad range of topics in metabolism research. It aims to advance the understanding of metabolic and homeostatic processes at a cellular and physiological level. The journal publishes research from various fields, including fundamental cell biology, basic biomedical and translational research, and integrative physiology. It focuses on how cellular metabolism affects cellular function, the physiology and homeostasis of organs and tissues, and the regulation of organismal energy homeostasis. It also investigates the molecular pathophysiology of metabolic diseases such as diabetes and obesity, as well as their treatment. Nature Metabolism follows the standards of other Nature-branded journals, with a dedicated team of professional editors, rigorous peer-review process, high standards of copy-editing and production, swift publication, and editorial independence. The journal has a high impact factor, has a certain influence in the international area, and is deeply concerned and cited by the majority of scholars.