Table 1.
Conservation of proteins involved in maintaining mitochondrial iron homeostasis. (SA = sideroblastic anemia; MMDS = multiple mitochondrial dysfunctions syndrome).
| Pathway | S. cerevisiae | Mammalian | Function | Pathology |
|---|---|---|---|---|
| Mitochondrial Fe Import | Por1/Por2 | VDAC | Mitochondrial Fe import? | - |
| - | DMT1 | Mitochondrial Fe import | Hypochromic microcytic anemia [70,71,72] | |
| - | PCBP2 | Fe transporter | - | |
| Mrs3/Mrs4 | MFRN1/ MFRN2 |
IMM Fe importer | - | |
| Rim2 | - | IMM low-affinity Fe importer | - | |
| Mdl1 (peptide transporter) | ABCB10 | Stabilization of MFRN1/IMM biliverdin transporter in mammals? | - | |
| - | MCU | IMM Ca (Fe?) import | - | |
| - | SFXN1-5 | Similar and differing functions in serine transport and Fe transport across IMM | Mitochondriopathy; macrocytic anemia [73] |
|
| Mitochondrial Iron Storage | - | FTMT | Mitochondrial Fe storage | - |
| ISC Biogenesis and Maturation of ISC Proteins | Nfs1 | NFS1 | Cysteine desulfurase/sulfur donation | Combined oxidative phosphorylation deficiency [74,75] |
| Isd11 | ISD11 | Nfs1 stabilization/regulation | Combined oxidative phosphorylation deficiency [76] | |
| Acp1 | ACP1 | Nfs1 stabilization/regulation | - | |
| Yfh1 | FXN | Iron donation?/ISC biogenesis regulator | Friedreich’s ataxia [77,78,79,80,81,82,83] | |
| Isu1/Isu2 | ISCU | Core ISC biogenesis scaffold | Hereditary myopathy with lactic acidosis [84,85,86,87] |
|
| Yah1 | FDX2 | Electrons for ISC synthesis | Episodic mitochondrial myopathy [88,89] | |
| Arh1 | FDXR | Electrons for ISC synthesis | Auditory neuropathy; optic atrophy [90] |
|
| Ssq1 | HSPA9 | ISC transfer | SA [91,92] | |
| Jac1 | HSC20 | ISC transfer | - | |
| Mge1 | GRPEL1 | Nucleotide release factor for Ssq1/HSPA9 | - | |
| Grx5 | GLRX5 | ISC transfer | SA [93,94,95] | |
| Isa1 | ISCA1 | 4Fe-4S synthesis | MMDS [96,97] | |
| Isa2 | ISCA2 | 4Fe-4S synthesis | MMDS [98,99,100,101] | |
| Iba57 | IBA57 | 4Fe-4S synthesis | MMDS [102,103,104,105,106,107] | |
| Nfu1 | NFU1 | Maturation of ISC proteins | MMDS [108,109] | |
| - | NUBPL | Maturation of ISC proteins | Mitochondrial complex I deficiency [110,111,112,113] | |
| Bol3 | BOLA3 | Maturation of ISC proteins | MMDS 2 [108,114,115] | |
| Bol1 | BOLA1 | Maturation of ISC proteins | - | |
| Atm1 | ABCB7 | Fe or ISC intermediate export | SA with ataxia [116,117,118] | |
| - | ABCB8 | Fe or ISC intermediate export? | - | |
| Heme Biosynthesis and Modification | Hem15 | FECH | Final step in formation of heme b | Erythropoietic protoporphyria [119,120,121,122,123,124,125] |
| Cox10 | COX10 | Formation of heme o intermediate from heme b | Mitochondrial complex IV deficiency [126,127,128] | |
| Cox15 | COX15 | Formation of heme a from heme o intermediate | Mitochondrial complex IV deficiency [129,130,131,132] | |
| Cyc3/Cyt2 | HCCS | Heme installation in cytochrome c and cytochrome c1 | - | |
| Mitochondrial Fe Export | Mmt1/Mmt2 | - | Mitochondrial Fe export | - |
| Mtm1 | Slc25a39 | IMM Fe export | - | |
| - | FLVCR1b | Mitochondrial heme export? | - | |
| Dap1 | PGRMC1 | Cytosolic acceptor of mitochondrial heme? | - | |
| - | HBP-1 | Cytosolic acceptor of mitochondrial heme? | - |