Table 1. Assembly factors of the OXPHOS with their (predicted) functions and related mitochondrial disease.
| Gene/protein | OMIM | (Predicted) function(s)* | Associated phenotypes |
|---|---|---|---|
| CI assembly factors | |||
| NDUFAF1 | 606934 | CI chaperone; transient interaction with early arm membrane intermediates (ND2 module) | Cardiomyoencephalopathy, lactic acidosis; leukodystrophy, neuropathy |
| NDUFAF2 | 609653 | Stabilizer of late intermediate (N module) | Leukoencephalopathy with vanishing white matter, Leigh syndrome |
| NDUFAF3 | 612911 | Interacts with some CI subunits and with NDUFAF4 (Q module) | Variable phenotypes: macrocephaly, severe muscle weakness, myoclonic seizures, brain leukomalacia; Leigh syndrome |
| NDUFAF4 | 611776 | Interacts with some CI subunits and with NDUFAF3 (Q module) | Encephalopathy, antenatal cardiomyopathy, Leigh syndrome |
| NDUFAF5 | 612360 | Probable methyltransferase of NDUFS7; early arm membrane assembly | Leigh syndrome, progressive spasticity |
| NDUFAF6 | 612392 | Probable role in the assembly/stability of the Q module | Leigh syndrome; Acadian variant of Fanconi syndrome |
| NDUFAF7 | 615898 | Methyltransferase of NDUFS2; stabilizer of early intermediate(s) | Pathologic myopia |
| ACAD9 | 611103 | CI ND2 module assembler by the interaction with NDUFAF1, ECSIT and TMEM126B (MCIA) | Cardiomyopathy, encephalopathy, lactic acidosis, exercise intolerance |
| FOXRED1 | 613622 | Mid-late stages of CI assembly (ND4 module) | Leigh syndrome; microcephaly and cardiomyopathy |
| TIMMDC1 | 615534 | Assembly of membrane-embedded (ND1 module) and soluble arms of CI | Variable neurological phenotypes: Leigh syndrome; seizures, hypotonia, deafness, peripheral neuropathy, nystagmus |
| TMEM126B | 615533 | Assembly of the mature CI from the ND2 module 315- and 370-kDa subcomplexes | Exercise intolerance; cardiomyopathy and renal tubular acidosis |
| CII assembly factors | |||
| SDHAF1 | 612848 | Fe/S clusters insertion into SDHB | Leukoencephalopathy |
| SDHAF2 | 613019 | Flavination of SDHA | Hereditary paraganglioma |
| CIII assembly factors | |||
| BCS1L | 603647 | Incorporation of UQCRFS1 | GRACILE syndrome, Bjornstad syndrome, encephalopathy, proximal tubulopathy and liver failure |
| TTC19 | 613814 | Binding to fully assembled CIII dimer, role on UQCRFS1 turnover | Progressive encephalopathy, ataxia, psychiatric symptoms |
| LYRM7 | 615831 | Binding and stabilization of UQCRFS1 and interaction with components of an Fe–S transfer complex for CIII | Leukcoencephalopathy, liver failure |
| UQCC2 | 614461 | Interacts with UQCC1; synthesis of cyt b and the first steps of CIII assembly | Lactic acidosis, dysmorphic features; respiratory distress and seizures |
| UQCC3 | 616097 | Cardiolipin-binding protein; stabilizer of CIII and CIII supercomplexes | Lactic acidosis, hypoglycemia, hypotonia, and delayed development |
| CIV assembly factors | |||
| SURF1 | 185620 | Formation of the early MTCO1 subcomplexes | Leigh syndrome |
| COA3/MITRAC12 | 614775 | Interaction with early COX intermediates and assembly factors | Exercise intolerance and neuropathy |
| COA5/C2ORF64 | 613920 | Involved in a very early step of the COX assembly | Fatal neonatal cardiomyopathy |
| COA7 | 615623 | Unknown | Ataxia and neuropathy |
| COX14/c12orf62 | 614478 | Coupling synthesis of MTCO1 with assembly into COX holoenzyme | Respiratory and neurologic distress, metabolic acidosis and neonatal death |
| COX20/FAM36A | 614698 | Involved in early steps of the COX assembly; interaction with MTCO2 | Ataxia and muscle hypotonia, dystonia-ataxia |
| PET100 | 614770 | Involved in intermediate stage of COX assembly | Psychomotor delay, seizures, hypotonia, and Leigh syndrome |
| PET117 | 614771 | Coupling Heme a synthase activity to COX assembly. Interaction with PET100 | Neurodevelopmental regression |
| APOPT1 | 616003 | Unknown | Leukoencephalopathy |
| Copper incorporation | |||
| COA6 | 614772 | Copper homeostasis and transport to CIV | Fatal infantile cardioencephalomyopathy |
| SCO1 | 603644 | Incorporation of copper atoms in the catalytic sites of the nascent CIV | Infantile encephalopathy, neonatal hepatopathy, ketoacidotic comas |
| SCO2 | 604272 | Incorporation of copper atoms in the catalytic sites of the nascent CIV | Infantile cardioencephalomyopathy, myopia, CMT |
| Heme biosynthesis | |||
| COX10 | 602125 | Heme A synthesis (conversion of heme b into heme o) | Leigh syndrome, proximal renal tubulopathy, hypertrophic cardiomyopathy, sensorineural deafness, metabolic acidosis |
| COX15 | 603646 | Heme A synthesis (conversion of heme o into heme a) | Infantile cardiomyopathy, Leigh syndrome |
| CV assembly factors | |||
| ATPAF2 | 608918 | F1 chaperone; essential for assembly of α + β heterooligomer | Degenerative encephalopathy, connatal lactic acidosis, methyl glutaconic aciduria |
| TMEM70 | 612418 | Assembly of F1; structure of cristae | Neonatal encephalocardiomyopathy |
| Fe–S biosynthesis | |||
| BOLA3 | 613183 | Specific Fe–S cluster targetting factor | Epileptic encephalopathy, cardiomyopathy, spasticity (MMDS2) |
| FDXR | 103270 | Ferredoxin reductase | Auditory neuropathy, optic atrophy |
| FXN | 606829 | Iron chaperone | Friedreich’s ataxia |
| GLRX5 | 609588 | Fe–S cluster transfer to apoproteins | Sideroblastic anemia, spasticity |
| IBA57 | 615316 | Required for [4Fe–4S] cluster assembly | Leukodystrophy, hypotonia, dysmorphism, SPOAN (MMDS3) |
| ISCA1 | 611006 | Required for [4Fe–4S] cluster assembly | Leukodystrophy, epilepsy (MMDS5) |
| ISCA2 | 615317 | Required for [4Fe–4S] cluster assembly | Leukodystrophy (MMDS4) |
| ISCU | 611911 | Scaffold protein for Fe-S cluster synthesis | Myopathy, hypertrophic cardiomyopathy |
| LYRM4/ISD11 | 613311 | Fe-S protein biogenesis desulphurase interacting protein | Respiratory distress, hypotonia, hepatopathy |
| NFS1 | 603485 | Cysteine desulphurase | Lactic acidosis, hypotonia, multisystem organ failure |
| NFU1 | 608100 | Scaffold protein for [4Fe–4S] cluster synthesis | Hypotonia, leukodystrophy, epilepsy (MMDS1) |
| NUBPL | 613621 | Facilitates the assembly of Fe–S cofactors and subunits in CI | Leukodystrophy, myopathy, ataxia (CI deficiency) |
| Cofactor and cytochrome biosynthesis | |||
| HCCS | 300056 | Synthesis of cyt c1 and cyt c | MIDAS |
| CYCS | 123970 | cyt c | Thrombocytopenia |
| FLAD1 | 610595 | Synthesis of FAD | Lipid storage myopathy |
| CoQ10 | |||
| ADCK3/COQ8A | 606980 | CoQ10 biosynthesis | Cerebellar ataxia |
| ADCK4/COQ8B | 615567 | CoQ10 biosynthesis | Nephrotic syndrome, proteinuria |
| COQ2 | 609825 | Parahydroxybenzoate-polyprenyltransferase | Encephalomyopathy; cardiomyopathy and renal failure; ataxia; Leigh syndrome; isolated myopathy |
| COQ4 | 612898 | CoQ10 biosynthesis | Cardiac or neurologic involvement |
| COQ6 | 614647 | Flavin-dependent monooxygenase | Nephrotic syndrome, seizures |
| COQ7 | 601683 | Di-iron oxidase | Neonatal complex multisystem disorder |
| COQ9 | 612837 | CoQ10 biosynthesis | Encephalopathy, microcephaly |
| PDSS1 | 607429 | Trans-prenyltransferase (subunit 1) | Early-onset multisystem disorder |
| PDSS2 | 610564 | Trans-prenyltransferase (subunit 2) | Fatal encephalomyopathy and nephrotic syndrome |
Abbreviations: CMT, Charcot–Marie–Tooth; Fe–S, iron–sulphur; FOXRED, FAD-dependent oxidoreductase-containing domain 1; GRACILE, growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, early death; MIDAS, microphthalmia, dermal aplasia and sclerocornea; MMDS, multiple mitochondrial dysfunctions syndrome; NUBPL, nucleotide-binding protein like; SCO, synthesis of cytochrome oxidase 1; SCO2, synthesis of cytochrome oxidase 2; SDHAF, SDH assembly factor 1; SPOAN, spastic paraparesis, peripheral neuropathy ± optic nerve atrophy; UQCRFS1, Rieske Fe–S protein.
*
A detailed description of the functions of the assembly factors is reported in a dedicated paper by Signes and Fernandez-Vizarra [1] in this issue.