Figure 1.

Heme metabolism and Fe-S cluster biogenesis are interconnected. The ISC machinery (composed by ISCU2, FXN, and other 16 proteins) is responsible for the generation of Fe-S clusters necessary for several mitochondrial proteins (in orange), including those of the electron transport chain (ETC), some enzymes of the TCA cycle (ACO2 and SDHB) and LIAS. The ISC machinery is also responsible for the generation of a X-S compound that is exported in the cytosol by ABCB7 and used by the CIA machinery for the generation of Fe-S clusters to be incorporated into non-mitochondrial proteins. Heme is synthesized through eight enzymatic reactions occurring between mitochondria and cytosol. The availability of free heme is further controlled at the level of heme catabolism (HO1) and heme export (FLVCR1a and FLVCR1b). FLVCR1b has been drawn on both mitochondrial membranes, however its specific subcellular localization still remains to be determined. Although not shown in the picture other heme importers and exporters have been identified (see the text for details). Both heme and Fe-S clusters are necessary for the ETC activity. Interestingly, the biosynthetic pathways of the two cofactors are strongly interconnected. Indeed, heme synthesis depends on Fe-S clusters for succinyl-CoA supply, for the expression of ALAS1 and FECH. Whether Fe-S clusters biogenesis depends on heme is less clear.