COX15

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
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q24.2 Start 99,711,844 bp[1] End 99,732,100 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19|19 C3 Start 43,721,693 bp[2] End 43,741,439 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in caput epididymis corpus epididymis right uterine tube right adrenal gland left adrenal gland renal medulla body of tongue vastus lateralis muscle lactiferous duct gastric mucosa Top expressed in external carotid artery internal carotid artery seminal vesicula atrium epithelium of stomach soleus muscle barrel cortex ciliary body myocardium of ventricle intercostal muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytochrome-c oxidase activity oxidoreductase activity, acting on the CH-CH group of donors protein binding oxidoreductase activity, acting on NAD(P)H, heme protein as acceptor heme binding molecular adaptor activity Cellular component mitochondrial respirasome cytochrome complex integral component of membrane mitochondrial membranes mitochondrion membrane nucleus mitochondrial inner membrane Biological process cellular respiration proton transmembrane transport respiratory chain complex IV assembly heme biosynthetic process heme A biosynthetic process mitochondrial electron transport, cytochrome c to oxygen respiratory gaseous exchange by respiratory system Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1355 226139 Ensembl ENSG00000014919 ENSMUSG00000040018 UniProt Q7KZN9 Q8BJ03 RefSeq (mRNA) NM_004376 NM_078470 NM_001320974 NM_001320975 NM_001320976 NM_144874 RefSeq (protein) NP_001307903 NP_001307904 NP_001307905 NP_004367 NP_510870 NP_001358953 NP_001358954 NP_001358955 NP_001358956 NP_001358957 NP_659123 Location (UCSC) Chr 10: 99.71 – 99.73 Mb Chr 19: 43.72 – 43.74 Mb PubMed search [3] [4]
Wikidata
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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]

References

Further reading

External links

• Human COX15 genome location and COX15 gene details page in the UCSC Genome Browser.