The role of abnormal brain
iron metabolism in
neurodegenerative diseases is still insufficiently understood. Here, we investigate the molecular basis of the
neurodegenerative disease hereditary ferritinopathy (HF), in which dysregulation of brain
iron homeostasis is the primary cause of neurodegeneration. We mutagenized
ferritin's three-fold pores (3FPs), i.e. the main entry route for
iron, to investigate
ferritin's
iron management when
iron must traverse the
protein shell through the disrupted four-fold pores (4FPs) generated by mutations in the
ferritin light chain (FtL) gene in HF. We assessed the structure and properties of
ferritins using cryo-electron microscopy and a range of functional analyses in vitro. Loss of 3FP function did not alter
ferritin structure but led to a decrease in
protein solubility and
iron storage. Abnormal 4FPs acted as alternate routes for
iron entry and exit in the absence of functional 3FPs, further reducing
ferritin iron-storage capacity. Importantly, even a small number of MtFtL subunits significantly compromises
ferritin solubility and function, providing a rationale for the presence of
ferritin aggregates in cell types expressing different levels of FtLs in patients with HF. These findings led us to discuss whether modifying pores could be used as a pharmacological target in HF.