Fig. 2: Simplified overview of Fe-S cluster and heme biosynthesis.

Mitochondrial iron-sulfur (Fe-S) cluster biogenesis (left) is initiated by a protein complex, comprised of key proteins such as the ISCU scaffold, the cysteine desulfurase NFS1, and the allosteric activator FXN. This complex generates 2Fe-2S clusters, which are relayed to GLRX5. Subsequent machinery, comprising ISCA1, ISCA2, and IBA57, can build on these clusters to form 4Fe-4S clusters. Alternatively, some intermediate can be handed off to the cytosol via the inner membrane transporter ABCB7. Concurrently, heme biosynthesis (right) begins with the condensation of glycine and succinyl-CoA (Suc-CoA) to form 5-aminolevulinic acid (ALA). ALA is exported to the cytosol, potentially by ABCB10, where it undergoes further processing before being re-imported into the mitochondrial inner membrane space, possibly via ABCB6. Within this compartment, CPOX catalyzes the formation of protoporphyrin IX (PPIX), which is then transported to the mitochondrial matrix and converted to heme by FECH. PDB IDs for protein structures: ABCB7 (7VGF), GLRX5 (2WUL), FDX2 (2Y5C), LTRM4-NFS1-FXN-ISCU-ACP (8PK8), ABCB10 (7Y49), FECH (1HRK), PPOX (3NKS), CPOX (2AEX), ABCB6 (7DNY), and TMEM14 (2LOR).