A specialized pathway for erythroid iron delivery through lysosomal trafficking of transferrin receptor 2

Erythroid progenitors are the largest consumers of iron in the human body. In these cells, a high flux of iron must reach the mitochondrial matrix to form sufficient heme to support hemoglobinization. Canonical erythroid iron trafficking occurs via the first transferrin receptor (TfR1)-mediated endocytosis of diferric-transferrin into recycling endosomes, where ferric iron is released, reduced, and exported to the cytosol via DMT1. However, mice lacking TfR1 or DMT1 demonstrate residual erythropoiesis, suggesting additional pathways for iron use. How iron moves from endosomes to mitochondria is incompletely understood, with both cytosolic chaperoning and " kiss and run" interorganelle transfer implicated. TfR2, in contrast to its paralog TfR1, has established roles in iron sensing, but not iron uptake. Recently, mice with marrow-selective TfR2 deficiency were found to exhibit microcytosis, suggesting TfR2 may also contribute to erythroid hemoglobinization. In this study, we identify alternative trafficking, in which TfR2 mediates lysosomal transferrin delivery. Imaging studies reveal an erythroid lineage-specific organelle arrangement consisting of a focal lysosomal cluster surrounded by a nest of mitochondria, with direct contacts between these 2 organelles. Erythroid TfR2 deficiency yields aberrant mitochondrial morphology, implicating TfR2-dependent transferrin trafficking in mitochondrial maintenance. Human TFR2 shares a lineage-and stage-specific expression pattern with MCOLN1, encoding a lysosomal iron channel, and MFN2, encoding a protein mediating organelle contacts. Functional studies reveal these latter factors to be involved in mitochondrial regulation and erythroid differentiation, with Mfn2 required for mitochondrial-lysosomal contacts. These findings identify a new pathway for erythroid iron trafficking involving TfR2-mediated lysosomal delivery followed by interorganelle transfer to mitochondria.