Schematic illustration showing how Fe is acquired for cellular processes by the transferrin-transferrin receptor pathway in nonerythroid cells. Diferric transferrin (Tf) binds to the transferrin receptor 1 (TfR1) and is then internalized into cells by receptor-mediated endocytosis. After internalization, Fe is released from Tf by a decrease in endosomal pH and then transported through the endosomal membrane by the divalent metal ion transporter 1 (DMT1). Once transported into the cytosol, the Fe then becomes part of a poorly characterized labile Fe pool. The Fe can be either transported to ferritin, for storage and reutilization, or to the mitochondrion or other organelles such as the nucleus. Iron in the labile pool is thought to regulate the mRNA-binding activity of the iron-regulatory proteins (IRP1 and IRP2) that are important for regulating the expression of TfR1 and ferritin, which are critical for Fe uptake and storage, respectively.