Fig. 5.

Model of altered iron metabolism due to frataxin deficiency in MCK mutant hearts. Frataxin deficiency leads to increased mitochondrial-targeted iron uptake and cytosolic iron deficiency, facilitated by (i) Tfr1 up-regulation, increasing transferrin iron uptake; (ii) Fpn1 down-regulation, preventing iron release; (iii) Hmox1 up-regulation, increasing cytosolic heme catabolism; and (iv) Sec15l1 up-regulation, potentially aiding iron uptake. Iron is then taken up more avidly by the mitochondrion via increased Mfrn2. Moreover, there is down-regulation of 3 major pathways of mitochondrial iron utilization—ISC synthesis, heme synthesis from iron incorporation into protoporphyrin IX (PIX), and mitochondrial iron storage (Ftmt). The decreased iron utilization in these pathways reduces iron export from the mitochondrion as heme and ISCs. This suppression, together with increased iron uptake, decreased iron release, and iron targeting to the mitochondrion, leads to the marked mitochondrial iron loading (1).