A Bdh2-driven Lysosome to Mitochondria Iron Trafficking Controls Ferroptosis in Melanoma

A Bdh2-driven Lysosome to Mitochondria Iron Trafficking Controls Ferroptosis in Melanoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A Bdh2-driven Lysosome to Mitochondria Iron Trafficking Controls Ferroptosis in Melanoma Patrizia Agostinis, Francesca Rizzollo, Abril Escamilla-Ayala, and 19 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5345588/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Sep, 2025 Read the published version in Nature Metabolism → Version 1 posted You are reading this latest preprint version Abstract Iron sustains cancer cell phenotypic and metabolic plasticity, yet it also sensitizes the mesenchymal/drug-tolerant persister phenotype to ferroptosis. This posits that iron compartmentalization must be tightly regulated. However, the molecular machinery governing organelle Fe2+ compartmentalization remains elusive. Here, we identified Bdh2, the mammalian homolog of the bacterial EntA, as a key effector of inter-organelle Fe2+ redistribution and ferroptosis vulnerability during melanoma transition from a melanocytic (MEL) to a mesenchymal-like (MES) phenotype. In metabolically proficient MEL cells, Bdh2 localizes at the mitochondria-lysosome contacts to generate the siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA) that ferries iron into the mitochondria. Fe2+ transfer by Bdh2 endorses OXPHOS and ATP production, utilized by V-ATPase for lysosomal acidification and MLC maintenance. Loss of Bdh2 expression 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 through the bloodstream. Thus, we unveiled a Bdh2-dependent evolutionary-conserved mechanism that orchestrates inter-organelle Fe2+ transfer, linking metabolic regulation of lysosomal pH to the ferroptosis vulnerability of the MES/drug-tolerant persister cells. Biological sciences/Cancer/Cancer metabolism Biological sciences/Cell biology/Cell death iron membrane contact sites lysosomes mitochondria ferroptosis melanoma plasticity. Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Published Journal Publication published 16 Sep, 2025 Read the published version in Nature Metabolism → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5345588","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":371864371,"identity":"dee227e1-29a6-4d13-9059-76a0b8210fea","order_by":0,"name":"Patrizia 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