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

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.