COX15

Last updated
COX15
Identifiers
Aliases COX15 , CEMCOX2, COX15 cytochrome c oxidase assembly homolog, cytochrome c oxidase assembly homolog, cytochrome c oxidase assembly homolog COX15
External IDs OMIM: 603646 MGI: 1920112 HomoloGene: 5848 GeneCards: COX15
Orthologs
SpeciesHumanMouse
Entrez

1355

226139

Ensembl

ENSG00000014919

ENSMUSG00000040018

UniProt

Q7KZN9

Q8BJ03

RefSeq (mRNA)

NM_004376
NM_078470
NM_001320974
NM_001320975
NM_001320976

Contents

NM_144874

RefSeq (protein)

NP_659123

Location (UCSC) Chr 10: 99.71 – 99.73 Mb Chr 19: 43.72 – 43.74 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a protein that in humans is encoded by the COX15 gene. [5] [6] This protein localizes to the inner mitochondrial membrane and involved in heme A biosynthesis. [7] COX15 is also part of a three-component mono-oxygenase (ferredoxin, ferredoxin reductase, and COX15) that catalyses the hydroxylation of the methyl group at position eight of the protoheme molecule. [7] Mutations in this gene has been reported in patients with hypertrophic cardiomyopathy as well as Leigh syndrome, and characterized by delayed onset of symptoms, hypotonia, feeding difficulties, failure to thrive, motor regression, and brain stem signs. [8] [9] [10]

Structure

Gene

The COX15 gene lies on the chromosome location of 10q24 and consists of nine exons. Two splice variants formed by alternative splicing at exon 9, COX15.1 and COX15.2, differ in the C-terminal domain of the protein and the 39-UTR of the transcript. But the functional significance of the different isoforms is still unknown. [5]

Protein

The COX15 protein localizes to the inner mitochondrial membrane and has several predicted transmembrane domains. [5] [11] Four conserved histidine residues are proven to be critical for COX15 activity. Both COX15 multimerization and enzymatic activity would be impaired if the 20-residue linker region connecting the two conserved domains of COX15 is removed. [12]

Function

COX15 is one of the cytochrome c oxidase (COX) assembly factors identified in yeast, playing a key role in the biosynthetic pathway of mitochondrial heme A, the prosthetic group of cytochrome a and a3. COX15 in yeast mediates hydroxylation of the methyl group at the C-8 position of the heme O molecule to form heme A. A deletion of COX15 results in undetectable levels of heme A but detectable levels of heme O. Similar findings are observed in patients with COX15 deletion mutants, suggesting a similar functional role for COX15 in mammalian mitochondria and a similar pathogenesis for the COX deficiency. [8] In complex IV of the respiratory chain, heme A is required for the proper folding of the Cox 1 subunit and subsequent assembly. A deficiency in the formation of heme A and functional COX would lead to impaired electron transport and oxidative phosphorylation. [13] COX15 multimerization is important for heme A biosynthesis and/or transfer to maturing COX. [12]

Clinical significance

COX deficiency is one of the most frequent causes of electron transport chain defects in humans. Therefore, in highly energy-demanding organs and tissues, such as brain and retinal tissue, with mutations in COX15, different clinical phenotypes are presented, such as early onset, fatal hypertrophic cardiomyopathy, [8] Leigh syndrome, [10] and encephalopathy. [14] Signs and symptoms of these diseases that can manifest include lactic acidosis, ataxia, hypotonia, seizures, respiratory distress, psychomotor retardation, vision loss, eye movement abnormalities, dysphagia, and central nervous system lesions. [15] [16] A sequence variation in COX15 has also been reported to associate with determining the genetic risk for Alzheimer’s disease development. [17]

Interactions

COX15 associates with Shy1 in distinct complexes, C-terminal epitope tagging of COX15 selectively affects its association to cytochrome c oxidase assembly intermediates (COA complexes). COX15 also forms complexes with maturing COX1, the heme-receiving subunit of COX, in the absence of Shy1. [18] COX15 is positively regulated by intracellular heme levels via Huntingtin-associated protein 1. [19]

Related Research Articles

<span class="mw-page-title-main">Cytochrome c oxidase</span> Complex enzyme found in bacteria, archaea, and mitochondria of eukaryotes

The enzyme cytochrome c oxidase or Complex IV, is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.

<span class="mw-page-title-main">Leigh syndrome</span> Mitochondrial metabolism disease characterized by progressive loss of mental and movement abilities

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily.

<span class="mw-page-title-main">MT-RNR1</span> SSU rRNA of the mitochondrial ribosome

Mitochondrially encoded 12S ribosomal RNA, also known as Mitochondrial-derived peptide MOTS-c or Mitochondrial open reading frame of the 12S rRNA-c is the SSU rRNA of the mitochondrial ribosome. In humans, 12S is encoded by the MT-RNR1 gene and is 959 nucleotides long. MT-RNR1 is one of the 37 genes contained in animal mitochondria genomes. Their 2 rRNA, 22 tRNA and 13 mRNA genes are very useful in phylogenetic studies, in particular the 12S and 16S rRNAs. The 12S rRNA is the mitochondrial homologue of the prokaryotic 16S and eukaryotic nuclear 18S ribosomal RNAs. Mutations in the MT-RNR1 gene may be associated with hearing loss.

<span class="mw-page-title-main">Cytochrome c oxidase subunit I</span> Enzyme of the respiratory chain encoded by the mitochondrial genome

Cytochrome c oxidase I (COX1) also known as mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein that in humans is encoded by the MT-CO1 gene. In other eukaryotes, the gene is called COX1, CO1, or COI. Cytochrome c oxidase I is the main subunit of the cytochrome c oxidase complex. Mutations in MT-CO1 have been associated with Leber's hereditary optic neuropathy (LHON), acquired idiopathic sideroblastic anemia, Complex IV deficiency, colorectal cancer, sensorineural deafness, and recurrent myoglobinuria.

<span class="mw-page-title-main">Cytochrome c oxidase subunit 2</span> Enzyme of the respiratory chain encoded by the mitochondrial genome

Cytochrome c oxidase subunit 2, also known as cytochrome c oxidase polypeptide II, is a protein that in humans is encoded by the MT-CO2 gene. Cytochrome c oxidase subunit II, abbreviated COXII, COX2, COII, or MT-CO2, is the second subunit of cytochrome c oxidase. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits of respiratory complex IV.

<span class="mw-page-title-main">Cytochrome c oxidase subunit III</span> Enzyme of the respiratory chain encoded by the mitochondrial genome

Cytochrome c oxidase subunit III (COX3) is an enzyme that in humans is encoded by the MT-CO3 gene. It is one of main transmembrane subunits of cytochrome c oxidase. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits of respiratory complex IV. Variants of it have been associated with isolated myopathy, severe encephalomyopathy, Leber hereditary optic neuropathy, mitochondrial complex IV deficiency, and recurrent myoglobinuria.

<span class="mw-page-title-main">SURF1</span> Protein-coding gene in the species Homo sapiens

Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the SURF1 gene. The protein encoded by SURF1 is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex, which is involved in the regulation of cytochrome c oxidase assembly. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency, and Charcot-Marie-Tooth disease 4K (CMT4K).

<span class="mw-page-title-main">SCO2</span>

SCO2 cytochrome c oxidase assembly is a protein that in humans is encoded by the SCO2 gene. The encoded protein is one of the cytochrome c oxidase (COX)(Complex IV) assembly factors. Human COX is a multimeric protein complex that requires several assembly factors. Cytochrome c oxidase (COX) catalyzes the transfer of electrons from cytochrome c to molecular oxygen, which helps to maintain the proton gradient across the inner mitochondrial membrane that is necessary for aerobic ATP production. The encoded protein is a metallochaperone that is involved in the biogenesis of cytochrome c oxidase subunit II. Mutations in this gene are associated with fatal infantile encephalocardiomyopathy and myopia 6.

<span class="mw-page-title-main">SCO1</span> Protein-coding gene in the species Homo sapiens

Protein SCO1 homolog, mitochondrial, also known as SCO1, cytochrome c oxidase assembly protein, is a protein that in humans is encoded by the SCO1 gene. SCO1 localizes predominantly to blood vessels, whereas SCO2 is barely detectable, as well as to tissues with high levels of oxidative phosphorylation. The expression of SCO2 is also much higher than that of SCO1 in muscle tissue, while SCO1 is expressed at higher levels in liver tissue than SCO2. Mutations in both SCO1 and SCO2 are associated with distinct clinical phenotypes as well as tissue-specific cytochrome c oxidase deficiency.

<span class="mw-page-title-main">COX6B1</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase subunit 6B1 is an enzyme that in humans is encoded by the COX6B1 gene. Cytochrome c oxidase 6B1 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. Mutations of the COX6B1 gene are associated with severe infantile encephalomyopathy and mitochondrial complex IV deficiency (MT-C4D).

<span class="mw-page-title-main">COX10</span> Mammalian protein found in Homo sapiens

Protoheme IX farnesyltransferase, mitochondrial is an enzyme that in humans is encoded by the COX10 gene. Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene, COX10, encodes heme A: farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A duplication and with HNPP deletion.

Mitochondrially encoded tRNA phenylalanine also known as MT-TF is a transfer RNA which in humans is encoded by the mitochondrial MT-TF gene.

Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrial MT-TK gene.

Mitochondrially encoded tRNA leucine 2 (CUN) also known as MT-TL2 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL2 gene.

<span class="mw-page-title-main">COX8A</span>

Cytochrome c oxidase subunit 8A (COX8A) is a protein that in humans is encoded by the COX8A gene. Cytochrome c oxidase 8A is a subunit of the cytochrome c oxidase complex, also known as Complex IV. Mutations in the COX8A gene have been associated with complex IV deficiency with Leigh syndrome and epilepsy.

<span class="mw-page-title-main">COA3</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase assembly factor 3, also known as Coiled-coil domain-containing protein 56, or Mitochondrial translation regulation assembly intermediate of cytochrome c oxidase protein of 12 kDa is a protein that in humans is encoded by the COA3 gene. This gene encodes a member of the cytochrome c oxidase assembly factor family. Studies of a related gene in fly suggest that the encoded protein is localized to mitochondria and is essential for cytochrome c oxidase function.

<span class="mw-page-title-main">COX14</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase assembly factor COX14 is a protein that in humans is encoded by the COX14 gene. This gene encodes a small single-pass transmembrane protein that localizes to mitochondria. This protein may play a role in coordinating the early steps of cytochrome c oxidase subunit assembly and, in particular, the synthesis and assembly of the COX I subunit of the holoenzyme. Mutations in this gene have been associated with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants.

Cytochrome c oxidase assembly factor COX20 is a protein that in humans is encoded by the COX20 gene. This gene encodes a protein that plays a role in the assembly of cytochrome c oxidase, an important component of the respiratory pathway. Mutations in this gene can cause mitochondrial complex IV deficiency. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants.

<span class="mw-page-title-main">COA6</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase assembly factor 6 is a protein that in humans is encoded by the COA6 gene. Mitochondrial respiratory chain Complex IV, or cytochrome c oxidase, is the component of the respiratory chain that catalyzes the transfer of electrons from intermembrane space cytochrome c to molecular oxygen in the matrix and as a consequence contributes to the proton gradient involved in mitochondrial ATP synthesis. The COA6 gene encodes an assembly factor for mitochondrial complex IV and is a member of the cytochrome c oxidase subunit 6B family. This protein is located in the intermembrane space, associating with SCO2 and COX2. It stabilizes newly formed COX2 and is part of the mitochondrial copper relay system. Mutations in this gene result in fatal infantile cardioencephalomyopathy.

<span class="mw-page-title-main">PET100</span> Protein-coding gene in the species Homo sapiens

PET100 homolog is a protein that in humans is encoded by the PET100 gene. Mitochondrial complex IV, or cytochrome c oxidase, is a large transmembrane protein complex that is part of the respiratory electron transport chain of mitochondria. The small protein encoded by the PET100 gene plays a role in the biogenesis of mitochondrial complex IV. This protein localizes to the inner mitochondrial membrane and is exposed to the intermembrane space. Mutations in this gene are associated with mitochondrial complex IV deficiency. This gene has a pseudogene on chromosome 3. Alternative splicing results in multiple transcript variants.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000014919 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040018 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 Petruzzella V, Tiranti V, Fernandez P, Ianna P, Carrozzo R, Zeviani M (December 1998). "Identification and characterization of human cDNAs specific to BCS1, PET112, SCO1, COX15, and COX11, five genes involved in the formation and function of the mitochondrial respiratory chain". Genomics. 54 (3): 494–504. doi:10.1006/geno.1998.5580. PMID   9878253.
  6. ↑ "Entrez Gene: COX15 COX15 homolog, cytochrome c oxidase assembly protein (yeast)".
  7. 1 2 Barros MH, Carlson CG, Glerum DM, Tzagoloff A (March 2001). "Involvement of mitochondrial ferredoxin and Cox15p in hydroxylation of heme O". FEBS Letters. 492 (1–2): 133–8. doi:10.1016/s0014-5793(01)02249-9. PMID   11248251. S2CID   21826949.
  8. 1 2 3 Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, Kennaway NG, Shoubridge EA (January 2003). "Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy". American Journal of Human Genetics. 72 (1): 101–14. doi:10.1086/345489. PMC   378614 . PMID   12474143.
  9. ↑ Miryounesi M, Fardaei M, Tabei SM, Ghafouri-Fard S (June 2016). "Leigh syndrome associated with a novel mutation in the COX15 gene". Journal of Pediatric Endocrinology & Metabolism. 29 (6): 741–4. doi:10.1515/jpem-2015-0396. PMID   26959537. S2CID   28078188.
  10. 1 2 Oquendo CE, Antonicka H, Shoubridge EA, Reardon W, Brown GK (July 2004). "Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome". Journal of Medical Genetics. 41 (7): 540–4. doi:10.1136/jmg.2003.017426. PMC   1735852 . PMID   15235026.
  11. ↑ Glerum DM, Muroff I, Jin C, Tzagoloff A (July 1997). "COX15 codes for a mitochondrial protein essential for the assembly of yeast cytochrome oxidase". The Journal of Biological Chemistry. 272 (30): 19088–94. doi: 10.1074/jbc.272.30.19088 . PMID   9228094.
  12. 1 2 Swenson S, Cannon A, Harris NJ, Taylor NG, Fox JL, Khalimonchuk O (May 2016). "Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into Its Function in Eukaryotes". The Journal of Biological Chemistry. 291 (19): 10411–25. doi: 10.1074/jbc.M115.707539 . PMC   4858986 . PMID   26940873.
  13. ↑ Kim HJ, Khalimonchuk O, Smith PM, Winge DR (September 2012). "Structure, function, and assembly of heme centers in mitochondrial respiratory complexes". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (9): 1604–16. doi:10.1016/j.bbamcr.2012.04.008. PMC   3601904 . PMID   22554985.
  14. ↑ Alfadhel M, Lillquist YP, Waters PJ, Sinclair G, Struys E, McFadden D, Hendson G, Hyams L, Shoffner J, Vallance HD (April 2011). "Infantile cardioencephalopathy due to a COX15 gene defect: report and review". American Journal of Medical Genetics. Part A. 155A (4): 840–4. doi:10.1002/ajmg.a.33881. PMID   21412973. S2CID   5541407.
  15. ↑ "COX15 - Cytochrome c oxidase assembly protein COX15 homolog - Homo sapiens (Human) - COX15 gene & protein". www.uniprot.org. Retrieved 2018-08-22. CC BY icon-80x15.png  This article incorporates text available under the CC BY 4.0 license.
  16. ↑ "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC   5210571 . PMID   27899622.
  17. ↑ Vitali M, Venturelli E, Galimberti D, Benerini Gatta L, Scarpini E, Finazzi D (December 2009). "Analysis of the genes coding for subunit 10 and 15 of cytochrome c oxidase in Alzheimer's disease". Journal of Neural Transmission. 116 (12): 1635–41. doi:10.1007/s00702-009-0324-8. PMID   19826901. S2CID   21914035.
  18. ↑ Bareth B, Dennerlein S, Mick DU, Nikolov M, Urlaub H, Rehling P (October 2013). "The heme a synthase Cox15 associates with cytochrome c oxidase assembly intermediates during Cox1 maturation" (PDF). Molecular and Cellular Biology. 33 (20): 4128–37. doi:10.1128/MCB.00747-13. PMC   3811676 . PMID   23979592.
  19. ↑ Wang Z, Wang Y, Hegg EL (January 2009). "Regulation of the heme A biosynthetic pathway: differential regulation of heme A synthase and heme O synthase in Saccharomyces cerevisiae". The Journal of Biological Chemistry. 284 (2): 839–47. doi: 10.1074/jbc.M804167200 . PMC   2613620 . PMID   18953022.

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