A direct, MFRN-independent Fe(II) transfer pathway at mitochondria-lysosome contacts

Abstract

Mitochondrial iron homeostasis is fundamental to respiration and redox balance, and its dysregulation is implicated in neurodegeneration, cardiomyopathy, and metabolic diseases 1, 2. Although lysosomes harbor the major cellular iron reservoir 3, 4, the prevailing model holds that mitochondria acquire Fe(II) directly from the cytosolic labile iron pool (LIP)5 via MFRN transporters6,7. Here, we challenge the canonical view by identifying a direct, MFRN-independent Fe(II) transfer pathway at mitochondria-lysosome contacts (MLCs) 8, 9. This PPS39/TOMM22/SFXN1-coordinated pathway enables lysosome-to-mitochondria Fe(II) flux bypassing the cytosolic LIP. Using live-cell structured illumination microscopy (SIM), we visualize direct Fe(II) transfer specifically occurring at MLCs. Multiple lines of evidence confirm that PPS39 and TOMM22 stabilize MLCs, while SFXN1 serves as the core effector protein for this MLC-dependent Fe(II) transport. Notably, SFXN1 knockdown markedly reduces mitochondrial Fe(II) levels independent of its established serine transport function 10. This pathway reveals a major route for mitochondrial Fe(II) acquisition to support redox homeostasis7.