A 3-Hydroxybutyrate dehydrogenase 2 (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. This paper demonstrates that the mitochondrial protein BDH2 localizes at the mitochondrial-lysosomal contacts (MLC) to produce the siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA) which carries Ferro-ion from lysosomes to mitochondria. Loss of BHD2 disrupts the MLC dynamics resulting in overload of ferro-ions in lysosomes causing increased ferroptosis vulnerability. The paper from Patrizia Agostinis’ group provides mechanistic insights in the crucial role of lysosome-mitochondrial communication regulating ferroptosis sensitivity.
Rizzollo, F., Escamilla-Ayala, A., Fattorelli, N. et al. BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states. Nat Metab 7, 1851–1870 (2025). https://doi.org/10.1038/s42255-025-01352-4
