Fe-S cluster biogenesis and CSA. Intra- and extramitochondrial pathways of Fe-S cluster synthesis and assembly into apoproteins are shown in relation to 2 CSA phenotypes: XLSA/A and GLRX5 deficiency. Frataxin (FXN) is thought to facilitate the delivery of iron, transported into mitochondria by MFRN1, to an Fe-S cluster assembly complex that involves the scaffold protein ISCU, the mitochondrial HSP70 homolog HSPA9 and its cochaperone HSCB, and glutaredoxin 5 (GLRX5). Elemental sulfur for this process is derived from cysteine by the cysteine desulfurase complex that includes the ISCS and ISD11 proteins. Subsequent to the assembly of the cluster, NIF and ISCA1/2 and other proteins are required to deliver the nascent Fe-S cluster to mitochondrial apoproteins. An unknown component required for cytosolic Fe-S cluster assembly of mitochondria is transported by ABCB7 to the multiprotein cytosolic Fe-S cluster assembly machinery that involves IOP1, NUBP1, NUBP2, and CIAO1. Among the cytosolic Fe-S proteins is IRBP1, which exists in a form containing an Fe-S cluster that functions as a cytosolic aconitase and in a clusterless form that binds IRE RNA stem-loop structures, thereby controlling translation or degradation of several mRNAs, including ALAS2.