Model of iron and IRP regulation in GLRX5-deficient nonerythroid (top) and erythroid (bottom) cells. Mitochondria Fe/S cluster synthesis by GLRX5 and effect on cytosolic IRP1 and IRP2. ↑ and ↓ indicate increase or decrease, respectively. Small red circles are iron molecules. The arrows in bold indicate direction of movements, whereas dotted arrows indicate decreased effect. (Top) Impaired Fe/S cluster synthesis in nonerythroid cells activates cytosolic IRP1, leading to high cellular iron import. High iron levels degrade IRP2. Iron levels are increased at a similar extent both in the cytosol and the mitochondria. (Bottom) IRP1 activation occurs as in nonerythroid cells. Imported iron is directed to mitochondria, due to heme deficiency secondary to ALAS2 repression. Low heme allows high IRP2 activity, which potentiates the IRP1 effects (red arrows). This vicious circle may be relieved by DFO treatment (boxed on the left), which shifts iron to the cytosol, modulating IRP2 activity. See “Discussion” for details. GLRX5 indicates glutaredoxin-5; Ft, ferritin; TfR1, transferrin receptor; MtFt, mitochondrial ferritin; ALAS2, aminolevulinic-acid-synthase-2; and DFO, deferoxamine.