COX6A1

COX6A1
Identifiers
Aliases	COX6A1 , COX6A, COX6AL, CMTRID, cytochrome c oxidase subunit 6A1
External IDs	OMIM: 602072 MGI: 103099 HomoloGene: 3219 GeneCards: COX6A1
Gene location (Human)
Chr.	Chromosome 12 (human)
End	120,440,737 bp
Gene location (Mouse)
Chr.	Chromosome 5 (mouse)
End	115,487,040 bp
RNA expression pattern
	Top expressed in
	prefrontal cortex; ; amygdala; ; dorsolateral prefrontal cortex; ; Brodmann area 9; ; substantia nigra; ; superior frontal gyrus; ; hippocampus proper; ; hypothalamus; ; putamen; ; nucleus accumbens;
	Top expressed in
	facial motor nucleus; ; condyle; ; Paneth cell; ; endocardial cushion; ; fossa; ; substantia nigra; ; Epithelium of stomach; ; atrioventricular valve; ; internal carotid artery; ; brown adipose tissue;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	cytochrome-c oxidase activity ; enzyme regulator activity ;
Cellular component	membrane ; mitochondrial inner membrane ; mitochondrion ; mitochondrial respiratory chain complex IV ; integral component of membrane ;
Biological process	generation of precursor metabolites and energy ; proton transmembrane transport ; mitochondrial electron transport, cytochrome c to oxygen ; aerobic respiration ; regulation of catalytic activity ; electron transport chain ;
	Sources:Amigo / QuickGO
Orthologs
	1337
	12861
	ENSG00000111775
	ENSMUSG00000041697
	P12074
	P43024
	NM_004373
	NM_007748
	NP_004364 ; NP_004364.2
	NP_031774
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated March 04, 2023

Cytochrome c oxidase subunit 6A1, mitochondrial is a protein that in humans is encoded by the COX6A1 gene. Cytochrome c oxidase 6A1 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. A mutation of the COX6A1 gene is associated with a recessive axonal or mixed form of Charcot-Marie-Tooth disease.^[5]^[6]

Structure

The COX6A1 gene, located on the q arm of chromosome 12 in position 24.2, contains 3 exons and is 2,653 base pairs in length.^[5] The COX6A1 protein weighs 12 kDa and is composed of 109 amino acids.^[7]^[8] The protein is a subunit of Complex IV, a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. This nuclear gene encodes polypeptide 1 (liver isoform) of subunit VIa, and polypeptide 1 is found in all non-muscle tissues. Polypeptide 2 (heart/muscle isoform) of subunit VIa is encoded by a different gene, COX6A2, and is present only in striated muscles. These two polypeptides share 66% amino acid sequence identity.^[5]

Function

Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane to drive ATP synthesis via protonmotive force. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex.^[5]

Summary reaction:

4 Fe²⁺-cytochrome c + 8 H⁺_in + O₂ → 4 Fe³⁺-cytochrome c + 2 H₂O + 4 H⁺_out^[9]

Clinical significance

A mutation leading to a 5 base pair deletion in the COX6A1 gene is associated with Charcot-Marie-Tooth disease (CMT). CMT is the most common inherited neuropathy and can result from mutations in over 30 different loci. Expression of COX6A1 is significantly reduced in affected individuals.^[10]

The Trans-activator of transcription protein (Tat) of human immunodeficiency virus (HIV) inhibits cytochrome c oxidase (COX) activity in permeabilized mitochondria isolated from both mouse and human liver, heart, and brain samples. Rapid loss of membrane potential (ΔΨ_m) occurs with submicromolar doses of Tat, and cytochrome c is released from the mitochondria.^[11]

Related Research Articles

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.

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.

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).

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.

Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1) is an enzyme that in humans is encoded by the COX4I1 gene. COX4I1 is a nuclear-encoded isoform of cytochrome c oxidase (COX) subunit 4. Cytochrome c oxidase is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Antibodies against COX4 can be used to identify the inner membrane of mitochondria in immunofluorescence studies. Mutations in COX4I1 have been associated with COX deficiency and Fanconi anemia.

Cytochrome c oxidase subunit 4 isoform 2, mitochondrial is an enzyme that in humans is encoded by the COX4I2 gene. COX4I2 is a nuclear-encoded isoform of cytochrome c oxidase (COX) subunit 4. Cytochrome c oxidase is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Mutations in COX4I2 have been associated with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (EPIDACH).

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).

Cytochrome c oxidase polypeptide 7A2, mitochondrial is an enzyme that in humans is encoded by the COX7A2 gene.

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.

Cytochrome c oxidase subunit 5B, mitochondrial is an enzyme in humans that is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. In humans, cytochrome c oxidase subunit 5B is encoded by the COX5B gene.

Cytochrome c oxidase polypeptide 7A1, mitochondrial is an enzyme that in humans is encoded by the COX7A1 gene.

Cytochrome c oxidase subunit 7B, mitochondrial (COX7B) is an enzyme that in humans is encoded by the COX7B gene. COX7B is a nuclear-encoded subunit of cytochrome c oxidase (COX). Cytochrome c oxidase is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Work with Oryzias latices has linked disruptions in COX7B with microphthalmia with linear skin lesions (MLS), microcephaly, and mitochondrial disease. Clinically, mutations in COX7B have been associated with linear skin defects with multiple congenital anomalies.

Cytochrome c oxidase subunit 7A-related protein, mitochondrial is an enzyme that in humans is encoded by the COX7A2L gene.

Cytochrome c oxidase subunit 7C, mitochondrial is an enzyme that in humans is encoded by the COX7C gene.

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. This protein localizes to the inner mitochondrial membrane and involved in heme A biosynthesis. COX15 is also part of a three-component mono-oxygenase that catalyses the hydroxylation of the methyl group at position eight of the protoheme molecule. 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.

Cytochrome c oxidase subunit 5a is a protein that in humans is encoded by the COX5A gene. Cytochrome c oxidase 5A is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.

Cytochrome c oxidase subunit VIa polypeptide 2 is a protein that in humans is encoded by the COX6A2 gene. Cytochrome c oxidase 6A2 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.

Cytochrome c oxidase subunit VIb polypeptide 2 is a protein that in humans is encoded by the COX6B2 gene. Cytochrome c oxidase 6B2 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.

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.

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.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000111775 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000041697 - Ensembl, May 2017
↑ "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.
1 2 3 4 "Entrez Gene: COX6A1 cytochrome c oxidase subunit VIa polypeptide 1".
↑ Hey Y, Hoggard N, Burt E, James LA, Varley JM (Sep 1997). "Assignment of COX6A1 to 6p21 and a pseudogene (COX6A1P) to 1p31.1 by in situ hybridization and somatic cell hybrids". Cytogenetics and Cell Genetics. 77 (3–4): 167–8. doi:10.1159/000134565. PMID 9284905.
↑ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475 . PMID 23965338.
↑ "Cytochrome c oxidase subunit 6A1, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 2018-07-20. Retrieved 2018-07-18.
↑ Voet D, Voet JG, Pratt CW (2013). "Chapter 18". Fundamentals of biochemistry: life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN 978-0-470-54784-7.
↑ Tamiya G, Makino S, Hayashi M, Abe A, Numakura C, Ueki M, Tanaka A, Ito C, Toshimori K, Ogawa N, Terashima T, Maegawa H, Yanagisawa D, Tooyama I, Tada M, Onodera O, Hayasaka K (Sep 2014). "A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease". American Journal of Human Genetics. 95 (3): 294–300. doi:10.1016/j.ajhg.2014.07.013. PMC 4157141 . PMID 25152455.
↑ Lecoeur H, Borgne-Sanchez A, Chaloin O, El-Khoury R, Brabant M, Langonné A, Porceddu M, Brière JJ, Buron N, Rebouillat D, Péchoux C, Deniaud A, Brenner C, Briand JP, Muller S, Rustin P, Jacotot E (2012). "HIV-1 Tat protein directly induces mitochondrial membrane permeabilization and inactivates cytochrome c oxidase". Cell Death & Disease. 3 (3): e282. doi:10.1038/cddis.2012.21. PMC 3317353 . PMID 22419111.

External links

Mass spectrometry characterization of COX6A1 at COPaKB
Human COX6A1 genome location and COX6A1 gene details page in the UCSC Genome Browser .
Overview of all the structural information available in the PDB for UniProt : P12074 (Cytochrome c oxidase subunit 6A1, mitochondrial) at the PDBe-KB .

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.

[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000111775 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000041697 - 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.

[entrez-5] 1 2 3 4 "Entrez Gene: COX6A1 cytochrome c oxidase subunit VIa polypeptide 1".

[pmid9284905-6] Hey Y, Hoggard N, Burt E, James LA, Varley JM (Sep 1997). "Assignment of COX6A1 to 6p21 and a pseudogene (COX6A1P) to 1p31.1 by in situ hybridization and somatic cell hybrids". Cytogenetics and Cell Genetics. 77 (3–4): 167–8. doi:10.1159/000134565. PMID 9284905.

[COPaKB-7] Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475 . PMID 23965338.

[url_COPaKB-8] "Cytochrome c oxidase subunit 6A1, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 2018-07-20. Retrieved 2018-07-18.

[Biochem-9] Voet D, Voet JG, Pratt CW (2013). "Chapter 18". Fundamentals of biochemistry: life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN 978-0-470-54784-7.

[10] Tamiya G, Makino S, Hayashi M, Abe A, Numakura C, Ueki M, Tanaka A, Ito C, Toshimori K, Ogawa N, Terashima T, Maegawa H, Yanagisawa D, Tooyama I, Tada M, Onodera O, Hayasaka K (Sep 2014). "A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease". American Journal of Human Genetics. 95 (3): 294–300. doi:10.1016/j.ajhg.2014.07.013. PMC 4157141 . PMID 25152455.

[11] Lecoeur H, Borgne-Sanchez A, Chaloin O, El-Khoury R, Brabant M, Langonné A, Porceddu M, Brière JJ, Buron N, Rebouillat D, Péchoux C, Deniaud A, Brenner C, Briand JP, Muller S, Rustin P, Jacotot E (2012). "HIV-1 Tat protein directly induces mitochondrial membrane permeabilization and inactivates cytochrome c oxidase". Cell Death & Disease. 3 (3): e282. doi:10.1038/cddis.2012.21. PMC 3317353 . PMID 22419111.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]