Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a
protein that in humans is encoded by the COX15gene.[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]
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^
abcPetruzzella 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.
PMID9878253.
^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.
PMID26959537.
S2CID28078188.
^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.
PMID21412973.
S2CID5541407.
^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.
PMID19826901.
S2CID21914035.
Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a
protein that in humans is encoded by the COX15gene.[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]
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^
abcPetruzzella 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.
PMID9878253.
^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.
PMID26959537.
S2CID28078188.
^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.
PMID21412973.
S2CID5541407.
^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.
PMID19826901.
S2CID21914035.