FIG. 4.

Fe transport and redox signaling. (a) Fe transport across the BBB occurs via DMT1 or by endocytosis of Tf- or Ft- bound Fe³⁺; followed by Fe release via the concerted action of Fpn with a ferroxidase, either Hp or sCp. Astrocytes modulate Fe transport through the production of sCp, sAPP, and hepcidin. sAPP stabilizes Fpn, while hepcidin induces its internalization. (b) Mitochondria are the organelles with highest demand of Fe. Although Fe transport into mitochondria is not fully understood, the recently demonstrated interaction between mitochondria and TfR-containing endosomes supports the “kiss and run” hypothesis. Inside the mitochondria, Fe crosses the inner membrane by Mfrn2. (c) In hippocampal neurons, NMDAR activation induces Ca²⁺ entry and NO^• production by nNOS, causing S-nitros(yl)ation of Dexras1, which in turn induces Fe uptake through DMT1 and TfR. (d) Increased intracellular Fe also induces H₂O₂ production, inducing Ca²⁺ release from ER via RyR, which is important for neuronal plasticity. Dexras1, Ras-related dexamethasone induced 1; ER, endoplasmic reticulum; Fe³⁺, ferric; Fpn, ferroportin; Ft, ferritin; H₂O₂, hydrogen peroxide; Hp, hephaestin; Mfrn2, mitoferrin-2; NO^•, nitric oxide; PAP7, peripheral benzodiazepine receptor-associated protein 7; RyR, ryanodine receptor; sAPP, soluble fragment of APP; sCp, soluble ceruloplasmin; Tf, transferrin; TfR: transferrin receptor.