Cytochrome c oxidase subunit I

Cytochrome c oxidase subunit I
PDB rendering based on 1occ.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1occ​, 1oco​, 1ocr​, 1ocz​, 1v54​, 1v55​, 2dyr​, 2dys​, 2eij​, 2eik​, 2eil​, 2eim​, 2ein​, 2occ​
Identifiers
Symbols	COX1 ; COI; MTCO1
External IDs	OMIM: 516030 MGI: 102504 HomoloGene: 5016 ChEMBL: 6173 GeneCards: COX1 Gene
Gene ontology Molecular function • cytochrome-c oxidase activity • iron ion binding • protein binding • electron carrier activity • heme binding Cellular component • mitochondrial inner membrane • integral to membrane • respiratory chain Biological process • mitochondrial electron transport, cytochrome c to oxygen • response to oxidative stress • aging • aerobic respiration • cerebellum development • respiratory electron transport chain • small molecule metabolic process • response to copper ion • response to electrical stimulus Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4512	17708
Ensembl	ENSG00000198804	ENSMUSG00000064351
UniProt	P00395	P00397
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	NP_904330
Location (UCSC)	Chr MT: 0.01 – 0.01 Mb	Chr MT: 0.01 – 0.01 Mb
PubMed search

Cytochrome c oxidase subunit I
Structure of the 13-subunit oxidized cytochrome c oxidase.[1]
Identifiers
Symbol	COX1 or COI
Pfam	PF00115
InterPro	IPR000883
PROSITE	PDOC00074
SCOP	1occ
SUPERFAMILY	1occ
TCDB	3.D.4
OPM superfamily	4
OPM protein	1v55
CDD	cd01663
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

"Cox1" redirects here. Particularly in a medical context, this can also refer to cyclooxygenase-1 (COX-1).

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.^[2] In other eukaryotes, the gene is called COX1, CO1, or COI.^[3] Cytochrome c oxidase I is the main subunit of the cytochrome c oxidase complex.

Function

Cytochrome c oxidase subunit I (CO1 or MT-CO1) is one of three mitochondrial DNA (mtDNA) encoded subunits (MT-CO1, MT-CO2, MT-CO3) of respiratory complex IV. Complex IV is the third and final enzyme of the electron transport chain of mitochondrial oxidative phosphorylation.^[2]

Cytochrome c oxidase (EC 1.9.3.1) is a key enzyme in aerobic metabolism. Proton pumping heme-copper oxidases represent the terminal, energy-transfer enzymes of respiratory chains in prokaryotes and eukaryotes. The CuB-heme a3 (or heme o) binuclear centre, associated with the largest subunit I of cytochrome c and ubiquinol oxidases (EC 1.10.3.10), is directly involved in the coupling between dioxygen reduction and proton pumping.^[4][5] Some terminal oxidases generate a transmembrane proton gradient across the plasma membrane (prokaryotes) or the mitochondrial inner membrane (eukaryotes).

The enzyme complex consists of 3-4 subunits (prokaryotes) up to 13 polypeptides (mammals) of which only the catalytic subunit (equivalent to mammalian subunit I (COI)) is found in all heme-copper respiratory oxidases. The presence of a bimetallic centre (formed by a high-spin heme and copper B) as well as a low-spin heme, both ligated to six conserved histidine residues near the outer side of four transmembrane spans within COI is common to all family members.^[6][7][8] In contrast to eukaryotes the respiratory chain of prokaryotes is branched to multiple terminal oxidases. The enzyme complexes vary in heme and copper composition, substrate type and substrate affinity. The different respiratory oxidases allow the cells to customize their respiratory systems according to a variety of environmental growth conditions.^[4]

It has been shown that eubacterial quinol oxidase was derived from cytochrome c oxidase in Gram-positive bacteria and that archaebacterial quinol oxidase has an independent origin. A considerable amount of evidence suggests that proteobacteria (Purple bacteria) acquired quinol oxidase through a lateral gene transfer from Gram-positive bacteria.^[4]

A related nitric-oxide reductase (EC 1.7.99.7) exists in denitrifying species of archaea and eubacteria and is a heterodimer of cytochromes b and c. Phenazine methosulphate can act as acceptor. It has been suggested that cytochrome c oxidase catalytic subunits evolved from ancient nitric oxide reductases that could reduce both nitrogen and oxygen.^[9][10]

Subfamilies

• Cytochrome c oxidase cbb3-type, subunit I IPR004677
• Cytochrome o ubiquinol oxidase, subunit I IPR014207
• Cytochrome aa3 quinol oxidase, subunit I IPR014233
• Cytochrome c oxidase, subunit I bacterial type IPR014241

Application

It is a gene that is often used as a DNA barcode to identify animal species. MT-CO1 gene sequence is suitable for this role because its mutation rate is often fast enough to distinguish closely related species and also because its sequence is conserved among conspecifics. Contrary to the primary objection raised by skeptics that MT-CO1 sequence differences are too small to be detected between closely related species, more than 2% sequence divergence is typically detected between such organisms,^[11] suggesting that the barcode is effective. In most if not all seed plants, however, the rate of evolution of cox1 is very slow.

MT-COI (CCOI) in colonic crypts

Colonic crypts (intestinal glands) within four tissue sections. The cells have been stained by immunohistochemistry to show a brown-orange color if the cells produce the mitochondrial protein cytochrome c oxidase subunit I (CCOI), and the nuclei of the cells (located at the outer edges of the cells lining the walls of the crypts) are stained blue-gray with haematoxylin. Panels A, B were cut across the long axes of the crypts and panels C, D were cut parallel to the long axes of the crypts. In panel A the bar shows 100 µm and allows an estimate of the frequency of crypts in the colonic epithelium. Panel B includes three crypts in cross-section, each with one segment deficient for CCOI expression and at least one crypt, on the right side, undergoing fission into two crypts. Panel C shows, on the left side, a crypt fissioning into two crypts. Panel D shows typical small clusters of two and three CCOI deficient crypts (the bar shows 50 µm). The images were made from original photomicrographs, but panels A, B and D were also included in an article^[12] and illustrations were published with Creative Commons Attribution-Noncommercial License allowing re-use.

CCOI is a synonym for MT-COI

CCOI protein is usually expressed at a high level in the cytoplasm of colonic crypts of the human large intestine (colon). However, CCOI is frequently lost in colonic crypts with age in humans and is also often absent in field defects that give rise to colon cancers as well as in portions of colon cancers.^[12]

The epithelial inner surface of the colon is punctuated by invaginations, the colonic crypts. The colon crypts are shaped like microscopic thick walled test tubes with a central hole down the length of the tube (the crypt lumen). Four tissue sections are shown in the image in this section, two cut across the long axes of the crypts and two cut parallel to the long axes.

Most of the human colonic crypts in the images have high expression of the brown-orange stained CCOI. However, in some of the colonic crypts all of the cells lack CCOI and appear mostly white, with their main color being the blue-gray staining of the nuclei at the outer walls of the crypts. Greaves et al.^[13] showed that deficiencies of CCOI in colonic crypts are due to mutations in the CCOI gene. As seen in panel B, a portion of the stem cells of three crypts appear to have a mutation in CCOI, so that 40% to 50% of the cells arising from those stem cells form a white segment in the cross-cut area.

In humans, the percent of colonic crypts deficient for CCOI is less than 1% before age 40, but then increases linearly with age.^[12] On average, the percent of colonic crypts deficient for CCOI reaches 18% in women and 23% in men by 80–84 years of age.^[12] Colonic tumors often arise in a field of crypts containing a large cluster (as many as 410) of CCOI-deficient crypts. In colonic cancers, up to 80% of tumor cells can be deficient in CCOI.^[12]

As seen in panels C and D, crypts are about 75 to about 110 cells long. The average crypt circumference is 23 cells.^[14] Based on these measurements, crypts have between 1725 to 2530 cells. Another report gave a range of 1500 to 4900 cells per colonic crypt.^[15]

The occurrence of frequent crypts with almost complete loss of CCOI in their 1700 to 5,000 cells suggests a process of natural selection. However, it has also been shown that a deficiency throughout a particular crypt due to an initial mitochondrial DNA mutation may occasionally occur through a stochastic process.^[16][17] Nevertheless, the frequent occurrence of CCOI deficiency in many crypts within a colon epithelium indicates that absence of CCOI likely provides a selective advantage.

CCOI is coded for by the mitochondrial chromosome. There are multiple copies of the chromosome in most mitochondria, usually between 2 and 6 per mitochondrion.^[18][19][20] If a mutation occurs in CCOI in one chomosome of a mitochondrion, there may be random segregation of the chromosomes during mitochondrial fission to generate new mitochondria. This can give rise to a mitochondrion with primarily or solely CCOI-mutated chromosomes.

A mitochondrion with largely CCOI-mutated chromosomes would need to have a positive selection bias in order to frequently become the main type of mitochondrion in a cell (a cell with CCOI-deficient homoplasmy). There are about 100 to 700 mitochondria per cell, depending on cell type.^[19][20] Furthermore, there is fairly rapid turnover of mitochondria, so that a mitochondrion with CCOI-mutated chromosomes and a positive selection bias could shortly become the major type of mitochondrion in a cell. The average half-life of mitochondria in rats, depending on cell type, is between 9 and 24 days,^[21] and in mice is about 2 days.^[22] In humans it is likely that the half life of mitochondria is also a matter of days to weeks.

A stem cell at the base of a colonic crypt that was largely CCOI-deficient may compete with the other 4 or 5 stem cells to take over the stem cell niche. If this occurs, then the colonic crypt would be deficient in CCOI in all 1700 to 5,000 cells, as is indicated for some crypts in panels A, B and D of the image.

Crypts of the colon can reproduce by fission, as seen in panel C, where a crypt is fissioning to form two crypts, and in panel B where at least one crypt appears to be fissioning. Most crypts deficient in CCOI are in clusters of crypts (clones of crypts) with two or more CCOI-deficient crypts adjacent to each other (see panel D).^[12] This illustrates that clones of deficient crypts often arise, and thus that there is likely a positive selective bias that has allowed them to spread in the human colonic epithelium.

It is not clear why a deficiency of CCOI should have a positive selective bias. One suggestion^[12] is that deficiency of CCOI in a mitochondrion leads to lower reactive oxygen production (and less oxidative damage) and this provides a selective advantage in competition with other mitochondria within the same cell to generate homoplasmy for CCOI-deficiency. Another suggestion was that cells with a deficiency in cytochrome c oxidase are apoptosis resistant, and thus more likely to survive. The linkage of CCOI to apoptosis arises because active cytochrome c oxidase oxidizes cytochrome c, which then activates pro-caspase 9, leading to apoptosis.^[23] These two factors may contribute to the frequent occurrence of CCOI-deficient colonic crypts with age or during carcinogenesis in the human colon.

Further reading

• Torroni A, Achilli A, Macaulay V; et al. (2006). "Harvesting the fruit of the human mtDNA tree". Trends Genet. 22 (6): 339–45. doi:10.1016/j.tig.2006.04.001. PMID 16678300.
• Bodenteich A, Mitchell LG, Polymeropoulos MH, Merril CR (1993). "Dinucleotide repeat in the human mitochondrial D-loop". Hum. Mol. Genet. 1 (2): 140. doi:10.1093/hmg/1.2.140-a. PMID 1301157.
• Brown MD, Yang CC, Trounce I; et al. (1992). "A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I". Am. J. Hum. Genet. 51 (2): 378–85. PMC 1682694. PMID 1322638.
• Lu X, Walker T, MacManus JP, Seligy VL (1992). "Differentiation of HT-29 human colonic adenocarcinoma cells correlates with increased expression of mitochondrial RNA: effects of trehalose on cell growth and maturation". Cancer Res. 52 (13): 3718–25. PMID 1377597.
• Marzuki S, Noer AS, Lertrit P; et al. (1992). "Normal variants of human mitochondrial DNA and translation products: the building of a reference data base". Hum. Genet. 88 (2): 139–45. doi:10.1007/bf00206061. PMID 1757091.
• Moraes CT, Andreetta F, Bonilla E; et al. (1991). "Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region". Mol. Cell. Biol. 11 (3): 1631–7. PMC 369459. PMID 1996112.
• Attardi G, Chomyn A, Doolittle RF; et al. (1987). "Seven unidentified reading frames of human mitochondrial DNA encode subunits of the respiratory chain NADH dehydrogenase". Cold Spring Harb. Symp. Quant. Biol. 51 (1): 103–14. doi:10.1101/sqb.1986.051.01.013. PMID 3472707.
• Chomyn A, Cleeter MW, Ragan CI; et al. (1986). "URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit". Science 234 (4776): 614–8. Bibcode:1986Sci...234..614C. doi:10.1126/science.3764430. PMID 3764430.
• Chomyn A, Mariottini P, Cleeter MW; et al. (1985). "Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase". Nature 314 (6012): 592–7. Bibcode:1985Natur.314..592C. doi:10.1038/314592a0. PMID 3921850.
• Sanger F, Coulson AR, Barrell BG; et al. (1981). "Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing". J. Mol. Biol. 143 (2): 161–78. doi:10.1016/0022-2836(80)90196-5. PMID 6260957.
• Montoya J, Ojala D, Attardi G (1981). "Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs". Nature 290 (5806): 465–70. Bibcode:1981Natur.290..465M. doi:10.1038/290465a0. PMID 7219535.
• Horai S, Hayasaka K, Kondo R; et al. (1995). "Recent African origin of modern humans revealed by complete sequences of hominoid mitochondrial DNAs". Proc. Natl. Acad. Sci. U.S.A. 92 (2): 532–6. Bibcode:1995PNAS...92..532H. doi:10.1073/pnas.92.2.532. PMC 42775. PMID 7530363.
• Gattermann N, Retzlaff S, Wang YL; et al. (1997). "Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia". Blood 90 (12): 4961–72. PMID 9389715.
• Bröker S, Meunier B, Rich P; et al. (1998). "MtDNA mutations associated with sideroblastic anaemia cause a defect of mitochondrial cytochrome c oxidase". Eur. J. Biochem. 258 (1): 132–8. doi:10.1046/j.1432-1327.1998.2580132.x. PMID 9851701.
• Andrews RM, Kubacka I, Chinnery PF; et al. (1999). "Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA". Nat. Genet. 23 (2): 147. doi:10.1038/13779. PMID 10508508.
• Karadimas CL, Greenstein P, Sue CM; et al. (2000). "Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA". Neurology 55 (5): 644–9. doi:10.1212/wnl.55.5.644. PMID 10980727.
• Ingman M, Kaessmann H, Pääbo S, Gyllensten U (2001). "Mitochondrial genome variation and the origin of modern humans". Nature 408 (6813): 708–13. doi:10.1038/35047064. PMID 11130070.
• Finnilä S, Lehtonen MS, Majamaa K (2001). "Phylogenetic network for European mtDNA". Am. J. Hum. Genet. 68 (6): 1475–84. doi:10.1086/320591. PMC 1226134. PMID 11349229.
• Maca-Meyer N, González AM, Larruga JM; et al. (2003). "Major genomic mitochondrial lineages delineate early human expansions". BMC Genet. 2: 13. doi:10.1186/1471-2156-2-13. PMC 55343. PMID 11553319.

References

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2. "Entrez Gene: Cytochrome c oxidase subunit I".
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21. Menzies RA, Gold PH (1971). "The turnover of mitochondria in a variety of tissues of young adult and aged rats". J. Biol. Chem. 246 (8): 2425–9. PMID 5553400.
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This article incorporates text from the public domain Pfam and InterPro IPR000883