{{short description|Enzyme of the respiratory chain encoded by the mitochondrial genome}} {{hatnote|"Cox1" redirects here. Particularly in a medical context, this can also refer to cyclooxygenase-1.}} {{Infobox_gene}} {{Pfam_box | Symbol = COX1 or COI | Name = Cytochrome c oxidase subunit I | image = PDB 1occ EBI.jpg | width = | caption = Structure of the 13-subunit oxidized cytochrome c oxidase.<ref name="pmid8638158">{{cite journal | vauthors = Tsukihara T, Aoyama H, Yamashita E, Tomizaki T, Yamaguchi H, Shinzawa-Itoh K, Nakashima R, Yaono R, Yoshikawa S | display-authors = 6 | title = The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A | journal = Science | volume = 272 | issue = 5265 | pages = 1136–1144 | date = May 1996 | pmid = 8638158 | doi = 10.1126/science.272.5265.1136 | s2cid = 20860573 | bibcode = 1996Sci...272.1136T }}</ref> | Pfam= PF00115 | InterPro= IPR000883 | SMART= | PROSITE = PDOC00074 | SCOP = 1occ | TCDB = 3.D.4 | OPM family= 4 | OPM protein= 1v55 | CDD = cd01663 }} thumb|320px|Location of the ''MT-CO1'' gene in the human mitochondrial genome. ''MT-CO1'' is one of the three cytochrome c oxidase subunit mitochondrial genes (orange boxes).
'''Cytochrome c oxidase I''' ('''COX1''') also known as '''mitochondrially encoded cytochrome c oxidase I''' ('''MT-CO1''') is a protein that is encoded by the ''MT-CO1'' gene in eukaryotes.<ref name="entrez">{{cite web | title = Entrez Gene: Cytochrome c oxidase subunit I | url = https://www.ncbi.nlm.nih.gov/gene/4512 }}</ref> The gene is also called '''''COX1''''', '''''CO1''''', or '''''COI'''''.<ref name="pmid22130576">{{cite journal | vauthors = Kosakyan A, Heger TJ, Leander BS, Todorov M, Mitchell EA, Lara E | title = COI barcoding of Nebelid testate amoebae (Amoebozoa: Arcellinida): extensive cryptic diversity and redefinition of the Hyalospheniidae Schultze | journal = Protist | volume = 163 | issue = 3 | pages = 415–434 | date = May 2012 | pmid = 22130576 | doi = 10.1016/j.protis.2011.10.003 | url = http://doc.rero.ch/record/28813/files/Kosakyan_Anush_-_COI_Barcoding_of_Nebelid_Testate_Amoebae_Amoebozoa_Arcellinida_20120321.pdf }}</ref> Cytochrome c oxidase I is the main subunit of the cytochrome c oxidase complex. In humans, 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.<ref name=":1" /><ref name=":0" /><ref name=":3" />
== Structure == In humans, the MT-CO1 gene is located from nucleotide pairs 5904 to 7444 on the guanine-rich heavy (H) section of mtDNA. The gene product is a 57 kDa protein composed of 513 amino acids.<ref name=COPaKB>{{cite journal | vauthors = 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 | display-authors = 6 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–1053 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref name="url_COPaKB">{{cite web | url = https://amino.heartproteome.org/web/protein/P00395 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = MT-CO1 - Cytochrome c oxidase subunit 1 }}{{Dead link|date=August 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>
== 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 cytochrome c oxidase, also known as complex IV. Cytochrome c oxidase ({{EC number|1.9.3.1}}) is a key enzyme in aerobic metabolism. It is the third and final enzyme of the electron transport chain of mitochondrial oxidative phosphorylation.<ref name="entrez" />
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 number|1.10.3.10}}), is directly involved in the coupling between dioxygen reduction and proton pumping.<ref name="PUB00002253">{{cite journal | vauthors = García-Horsman JA, Barquera B, Rumbley J, Ma J, Gennis RB | title = The superfamily of heme-copper respiratory oxidases | journal = Journal of Bacteriology | volume = 176 | issue = 18 | pages = 5587–5600 | date = September 1994 | pmid = 8083153 | pmc = 196760 | doi = 10.1128/jb.176.18.5587-5600.1994 }}</ref><ref name="PUB00006485">{{cite journal | vauthors = Papa S, Capitanio N, Glaser P, Villani G | title = The proton pump of heme-copper oxidases | journal = Cell Biology International | volume = 18 | issue = 5 | pages = 345–355 | date = May 1994 | pmid = 8049679 | doi = 10.1006/cbir.1994.1084 | s2cid = 36428993 }}</ref> 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.<ref name="PUB00001256">{{cite journal | vauthors = Castresana J, Lübben M, Saraste M, Higgins DG | title = Evolution of cytochrome oxidase, an enzyme older than atmospheric oxygen | journal = The EMBO Journal | volume = 13 | issue = 11 | pages = 2516–2525 | date = June 1994 | pmid = 8013452 | pmc = 395125 | doi = 10.1002/j.1460-2075.1994.tb06541.x }}</ref><ref name="PUB00000581">{{cite journal | vauthors = Capaldi RA, Malatesta F, Darley-Usmar VM | title = Structure of cytochrome c oxidase | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Bioenergetics | volume = 726 | issue = 2 | pages = 135–148 | date = July 1983 | pmid = 6307356 | doi = 10.1016/0304-4173(83)90003-4 | author3-link = Victor Darley-Usmar }}</ref><ref name="PUB00001153">{{cite journal | vauthors = Holm L, Saraste M, Wikström M | title = Structural models of the redox centres in cytochrome oxidase | journal = The EMBO Journal | volume = 6 | issue = 9 | pages = 2819–2823 | date = September 1987 | pmid = 2824194 | pmc = 553708 | doi = 10.1002/j.1460-2075.1987.tb02578.x }}</ref> 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.<ref name="PUB00002253"/>
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 Pseudomonadota (also known as proteobacteria or purple bacteria) acquired quinol oxidase through a lateral gene transfer from Gram-positive bacteria.<ref name="PUB00002253" />
A related nitric-oxide reductase ({{EC number|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.<ref name="pmid8137905">{{cite journal | vauthors = Saraste M, Castresana J | title = Cytochrome oxidase evolved by tinkering with denitrification enzymes | journal = FEBS Letters | volume = 341 | issue = 1 | pages = 1–4 | date = March 1994 | pmid = 8137905 | doi = 10.1016/0014-5793(94)80228-9 | s2cid = 1248917 | doi-access = free | bibcode = 1994FEBSL.341....1S }}</ref><ref name="pmid23044391">{{cite journal | vauthors = Chen J, Strous M | title = Denitrification and aerobic respiration, hybrid electron transport chains and co-evolution | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1827 | issue = 2 | pages = 136–144 | date = February 2013 | pmid = 23044391 | doi = 10.1016/j.bbabio.2012.10.002 | doi-access = free }}</ref>
== Clinical significance == Mutations in this gene in humans are associated with Leber's hereditary optic neuropathy (LHON), acquired idiopathic sideroblastic anemia, Complex IV deficiency, colorectal cancer, sensorineural deafness, and recurrent myoglobinuria.<ref name=":1">{{OMIM|516030}}</ref><ref name=":0" /><ref name=":3" />
=== Leber's hereditary optic neuropathy (LHON) === LHON, correlated with mutations in ''MT-CO1'', is characterized by optic nerve dysfunction, causing subacute or acute central vision loss. Some patients may display neurological or cardiac conduction defects. Because this disease is a result of mitochondrial DNA mutations affecting the respiratory chain complexes, it is inherited maternally.<ref>{{cite journal | vauthors = Brown MD, Yang CC, Trounce I, Torroni A, Lott MT, Wallace DC | title = A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I | journal = American Journal of Human Genetics | volume = 51 | issue = 2 | pages = 378–385 | date = August 1992 | pmid = 1322638 | pmc = 1682694 }}</ref><ref name=":0" /><ref name=":3" />
=== Acquired Idiopathic Sideroblastic Anemia === ''MT-CO1'' may be involved in the development of acquired idiopathic sideroblastic anemia. Mutations in mitochondrial DNA can cause respiratory chain dysfunction, preventing reduction of ferric iron to ferrous iron, which is required for the final step in mitochondrial biosynthesis of heme. The result is a ferric accumulation in mitochondria and insufficient heme production.<ref>{{cite journal | vauthors = Gattermann N, Retzlaff S, Wang YL, Hofhaus G, Heinisch J, Aul C, Schneider W | title = Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia | journal = Blood | volume = 90 | issue = 12 | pages = 4961–4972 | date = December 1997 | pmid = 9389715 | doi = 10.1182/blood.V90.12.4961 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bröker S, Meunier B, Rich P, Gattermann N, Hofhaus G | title = MtDNA mutations associated with sideroblastic anaemia cause a defect of mitochondrial cytochrome c oxidase | journal = European Journal of Biochemistry | volume = 258 | issue = 1 | pages = 132–138 | date = November 1998 | pmid = 9851701 | doi = 10.1046/j.1432-1327.1998.2580132.x | doi-access = }}</ref><ref name=":0" /><ref name=":3" />
=== Mitochondrial Complex IV deficiency (MT-C4D) === Mutations in this gene can cause mitochondrial Complex IV deficiency, a disease of the mitochondrial respiratory chain displaying a wide variety of clinical manifestations ranging from isolated myopathy to a severe multisystem disease affecting multiple organs and tissues. Symptoms may include liver dysfunction and hepatomegaly, hypotonia, muscle weakness, exercise intolerance, delayed motor development, mental retardation, developmental delay, and hypertrophic cardiomyopathy. In some patients, the hypertrophic cardiomyopathy is fatal at the neonatal stage. Other affected individuals may manifest Leigh disease.<ref>{{cite journal | vauthors = Varlamov DA, Kudin AP, Vielhaber S, Schröder R, Sassen R, Becker A, Kunz D, Haug K, Rebstock J, Heils A, Elger CE, Kunz WS | display-authors = 6 | title = Metabolic consequences of a novel missense mutation of the mtDNA CO I gene | journal = Human Molecular Genetics | volume = 11 | issue = 16 | pages = 1797–1805 | date = August 2002 | pmid = 12140182 | doi = 10.1093/hmg/11.16.1797 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lucioli S, Hoffmeier K, Carrozzo R, Tessa A, Ludwig B, Santorelli FM | title = Introducing a novel human mtDNA mutation into the Paracoccus denitrificans COX I gene explains functional deficits in a patient | journal = Neurogenetics | volume = 7 | issue = 1 | pages = 51–57 | date = March 2006 | pmid = 16284789 | doi = 10.1007/s10048-005-0015-z | s2cid = 21304246 }}</ref><ref name=":0" /><ref name=":3" />
=== Colorectal cancer (CRC) === ''MT-CO1'' mutations play a role in colorectal cancer, a very complex disease displaying malignant lesions in the inner walls of the colon and rectum. Numerous such genetic alterations are often involved with the progression of adenoma, or premalignant lesions, to invasive adenocarcinoma. Long-standing ulcerative colitis, colon polyps, and family history are risk factors for colorectal cancer.<ref name="pmid16407113"/><ref>{{cite journal | vauthors = Namslauer I, Brzezinski P | title = A mitochondrial DNA mutation linked to colon cancer results in proton leaks in cytochrome c oxidase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 9 | pages = 3402–3407 | date = March 2009 | pmid = 19218458 | pmc = 2651238 | doi = 10.1073/pnas.0811450106 | doi-access = free | bibcode = 2009PNAS..106.3402N }}</ref><ref name=":0" /><ref name=":3" />
=== Recurrent myoglobinuria mitochondrial (RM-MT) === RM-MT is a disease that is characterized by recurrent attacks of rhabdomyolysis (necrosis or disintegration of skeletal muscle) associated with muscle pain and weakness, exercise intolerance, low muscle capacity for oxidative phosphorylation, and followed by excretion of myoglobin in the urine. It has been associated with mitochondrial myopathy. A G5920A mutation, and a heteroplasmic G6708A nonsense mutation have been associated with COX deficiency and RM-MT.<ref>{{cite journal | vauthors = Karadimas CL, Greenstein P, Sue CM, Joseph JT, Tanji K, Haller RG, Taivassalo T, Davidson MM, Shanske S, Bonilla E, DiMauro S | display-authors = 6 | title = Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA | journal = Neurology | volume = 55 | issue = 5 | pages = 644–649 | date = September 2000 | pmid = 10980727 | doi = 10.1212/wnl.55.5.644 | s2cid = 26776388 }}</ref><ref>{{cite journal | vauthors = Kollberg G, Moslemi AR, Lindberg C, Holme E, Oldfors A | title = Mitochondrial myopathy and rhabdomyolysis associated with a novel nonsense mutation in the gene encoding cytochrome c oxidase subunit I | journal = Journal of Neuropathology and Experimental Neurology | volume = 64 | issue = 2 | pages = 123–128 | date = February 2005 | pmid = 15751226 | doi = 10.1093/jnen/64.2.123 | doi-access = free }}</ref><ref name=":0" /><ref name=":3" />
=== Deafness, sensorineural, mitochondrial (DFNM) === DFNM is a form of non-syndromic deafness with maternal inheritance. Affected individuals manifest progressive, postlingual, sensorineural hearing loss involving high frequencies. The mutation, A1555G, has been associated with this disease.<ref>{{cite journal | vauthors = Pandya A, Xia XJ, Erdenetungalag R, Amendola M, Landa B, Radnaabazar J, Dangaasuren B, Van Tuyle G, Nance WE | display-authors = 6 | title = Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia | journal = American Journal of Human Genetics | volume = 65 | issue = 6 | pages = 1803–1806 | date = December 1999 | pmid = 10577941 | pmc = 1288397 | doi = 10.1086/302658 }}</ref><ref name=":0" /><ref name=":3" />
== Subfamilies == * Cytochrome c oxidase cbb3-type, subunit I {{InterPro|IPR004677}} * Cytochrome o ubiquinol oxidase, subunit I {{InterPro|IPR014207}} * Cytochrome aa3 quinol oxidase, subunit I {{InterPro|IPR014233}} * Cytochrome c oxidase, subunit I bacterial type {{InterPro|IPR014241}}
== Use in DNA barcoding == ''MT-CO1'' is a gene that is often used as a DNA barcode to identify animal species. The ''MT-CO1'' gene sequence is suitable for this role because its mutation rate is generally 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 closely related animal species,<ref name="pmid12952648">{{cite journal | vauthors = Hebert PD, Ratnasingham S, deWaard JR | title = Barcoding animal life: cytochrome c oxidase subunit 1 divergences among closely related species | journal = Proceedings. Biological Sciences | volume = 270 | issue = Suppl 1 | pages = S96–S99 | date = August 2003 | pmid = 12952648 | pmc = 1698023 | doi = 10.1098/rsbl.2003.0025 }}</ref> suggesting that the barcode is effective for most animals. In most if not all seed plants, however, the rate of evolution of ''MT-CO1'' is very slow.<!-- sources in DNA barcoding article --> It has also been suggested that ''MT-CO1'' may be a better gene for DNA barcoding of soil fungi than ITS (the genetic region most commonly used for mycological barcoding).<ref name="Molitor2010">{{cite journal | vauthors = Molitor C, Inthavong B, Sage L, Geremia RA, Mouhamadou B | title = Potentiality of the cox1 gene in the taxonomic resolution of soil fungi | journal = FEMS Microbiology Letters | volume = 302 | issue = 1 | pages = 76–84 | date = January 2010 | pmid = 19909345 | doi = 10.1111/j.1574-6968.2009.01839.x | doi-access = free }}</ref>
== MT-COI (= CCOI) in colonic crypts == [[File:Colonic crypts within four tissue sections.jpg|thumb|400px|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, synonym for MT-COI), 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 MT-COI 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 MT-COI 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<ref name=Bernstein>{{cite journal | vauthors = Bernstein C, Facista A, Nguyen H, Zaitlin B, Hassounah N, Loustaunau C, Payne CM, Banerjee B, Goldschmid S, Tsikitis VL, Krouse R, Bernstein H | display-authors = 6 | title = Cancer and age related colonic crypt deficiencies in cytochrome c oxidase I | journal = World Journal of Gastrointestinal Oncology | volume = 2 | issue = 12 | pages = 429–442 | date = December 2010 | pmid = 21191537 | pmc = 3011097 | doi = 10.4251/wjgo.v2.i12.429 | doi-access = free }}</ref> and illustrations were published with Creative Commons Attribution-Noncommercial License allowing re-use.]]
The MT-COI protein, also known as CCOI, is usually expressed at a high level in the cytoplasm of colonic crypts of the human large intestine (colon). However, MT-COI 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.<ref name=Bernstein />
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 MT-COI. However, in some of the colonic crypts all of the cells lack MT-COI 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.<ref name="pmid16407113">{{cite journal | vauthors = Greaves LC, Preston SL, Tadrous PJ, Taylor RW, Barron MJ, Oukrif D, Leedham SJ, Deheragoda M, Sasieni P, Novelli MR, Jankowski JA, Turnbull DM, Wright NA, McDonald SA | display-authors = 6 | title = Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 3 | pages = 714–719 | date = January 2006 | pmid = 16407113 | pmc = 1325106 | doi = 10.1073/pnas.0505903103 | doi-access = free | bibcode = 2006PNAS..103..714G }}</ref> showed that deficiencies of MT-COI in colonic crypts are due to mutations in the MT-COI gene. As seen in panel B, a portion of the stem cells of three crypts appear to have a mutation in MT-COI, 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 MT-COI is less than 1% before age 40, but then increases linearly with age.<ref name=Bernstein /> On average, the percent of colonic crypts deficient for MT-COI reaches 18% in women and 23% in men by 80–84 years of age.<ref name=Bernstein /> Colonic tumors often arise in a field of crypts containing a large cluster (as many as 410) of MT-COI-deficient crypts. In colonic cancers, up to 80% of tumor cells can be deficient in MT-COI.<ref name=Bernstein />
As seen in panels C and D, crypts are about 75 to about 110 cells long. The average crypt circumference is 23 cells.<ref name=Baker>{{cite journal | vauthors = Baker AM, Cereser B, Melton S, Fletcher AG, Rodriguez-Justo M, Tadrous PJ, Humphries A, Elia G, McDonald SA, Wright NA, Simons BD, Jansen M, Graham TA | display-authors = 6 | title = Quantification of crypt and stem cell evolution in the normal and neoplastic human colon | journal = Cell Reports | volume = 8 | issue = 4 | pages = 940–947 | date = August 2014 | pmid = 25127143 | pmc = 4471679 | doi = 10.1016/j.celrep.2014.07.019 }}</ref> Based on these measurements, crypts have between 1725 and 2530 cells. Another report gave a range of 1500 to 4900 cells per colonic crypt.<ref name="pmid19878146">{{cite journal | vauthors = Nooteboom M, Johnson R, Taylor RW, Wright NA, Lightowlers RN, Kirkwood TB, Mathers JC, Turnbull DM, Greaves LC | display-authors = 6 | title = Age-associated mitochondrial DNA mutations lead to small but significant changes in cell proliferation and apoptosis in human colonic crypts | journal = Aging Cell | volume = 9 | issue = 1 | pages = 96–99 | date = February 2010 | pmid = 19878146 | pmc = 2816353 | doi = 10.1111/j.1474-9726.2009.00531.x }}</ref>
The occurrence of frequent crypts with almost complete loss of MT-COI 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.<ref name="pmid11976216">{{cite journal | vauthors = Coller HA, Bodyak ND, Khrapko K | title = Frequent intracellular clonal expansions of somatic mtDNA mutations: significance and mechanisms | journal = Annals of the New York Academy of Sciences | volume = 959 | issue = 1 | pages = 434–447 | date = April 2002 | pmid = 11976216 | doi = 10.1111/j.1749-6632.2002.tb02113.x | s2cid = 40639679 | bibcode = 2002NYASA.959..434C }}</ref><ref name="pmid11943860">{{cite journal | vauthors = Nekhaeva E, Bodyak ND, Kraytsberg Y, McGrath SB, Van Orsouw NJ, Pluzhnikov A, Wei JY, Vijg J, Khrapko K | display-authors = 6 | title = Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 8 | pages = 5521–5526 | date = April 2002 | pmid = 11943860 | pmc = 122802 | doi = 10.1073/pnas.072670199 | doi-access = free | bibcode = 2002PNAS...99.5521N }}</ref> Nevertheless, the frequent occurrence of MT-COI deficiency in many crypts within a colon epithelium indicates that absence of MT-COI likely provides a selective advantage.
MT-COI is coded for by the mitochondrial chromosome. There are multiple copies of the chromosome in most mitochondria, usually between 2 and 6 per mitochondrion.<ref name="pmid15138283">{{cite journal | vauthors = Legros F, Malka F, Frachon P, Lombès A, Rojo M | title = Organization and dynamics of human mitochondrial DNA | journal = Journal of Cell Science | volume = 117 | issue = Pt 13 | pages = 2653–2662 | date = June 2004 | pmid = 15138283 | doi = 10.1242/jcs.01134 | s2cid = 14335558 | doi-access = }}</ref><ref name=Robin>{{cite journal | vauthors = Robin ED, Wong R | title = Mitochondrial DNA molecules and virtual number of mitochondria per cell in mammalian cells | journal = Journal of Cellular Physiology | volume = 136 | issue = 3 | pages = 507–513 | date = September 1988 | pmid = 3170646 | doi = 10.1002/jcp.1041360316 | s2cid = 2841036 }}</ref><ref name=Satoh>{{cite journal | vauthors = Satoh M, Kuroiwa T | title = Organization of multiple nucleoids and DNA molecules in mitochondria of a human cell | journal = Experimental Cell Research | volume = 196 | issue = 1 | pages = 137–140 | date = September 1991 | pmid = 1715276 | doi = 10.1016/0014-4827(91)90467-9 }}</ref> If a mutation occurs in MT-COI in one chromosome 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 MT-COI-mutated chromosomes.
A mitochondrion with largely MT-COI-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 MT-COI-deficient homoplasmy). There are about 100 to 700 mitochondria per cell, depending on cell type.<ref name=Robin /><ref name=Satoh /> Furthermore, there is fairly rapid turnover of mitochondria, so that a mitochondrion with MT-COI-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,<ref name="pmid5553400">{{cite journal | vauthors = Menzies RA, Gold PH | title = The turnover of mitochondria in a variety of tissues of young adult and aged rats | journal = The Journal of Biological Chemistry | volume = 246 | issue = 8 | pages = 2425–2429 | date = April 1971 | pmid = 5553400 | doi = 10.1016/S0021-9258(18)62305-1 | doi-access = free }}</ref> and in mice is about 2 days.<ref name="pmid18691181">{{cite journal | vauthors = Miwa S, Lawless C, von Zglinicki T | title = Mitochondrial turnover in liver is fast in vivo and is accelerated by dietary restriction: application of a simple dynamic model | journal = Aging Cell | volume = 7 | issue = 6 | pages = 920–923 | date = December 2008 | pmid = 18691181 | pmc = 2659384 | doi = 10.1111/j.1474-9726.2008.00426.x }}</ref> 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 MT-COI-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 MT-COI 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 MT-COI are in clusters of crypts (clones of crypts) with two or more MT-COI-deficient crypts adjacent to each other (see panel D).<ref name=Bernstein /> 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 MT-COI should have a positive selective bias. One suggestion<ref name=Bernstein /> is that deficiency of MT-COI 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 MT-COI-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 MT-COI to apoptosis arises because active cytochrome c oxidase oxidizes cytochrome c, which then activates pro-caspase 9, leading to apoptosis.<ref name="pmid18439415">{{cite journal | vauthors = Brown GC, Borutaite V | title = Regulation of apoptosis by the redox state of cytochrome c | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1777 | issue = 7–8 | pages = 877–881 | year = 2008 | pmid = 18439415 | doi = 10.1016/j.bbabio.2008.03.024 | doi-access = free }}</ref> These two factors may contribute to the frequent occurrence of MT-COI-deficient colonic crypts with age or during carcinogenesis in the human colon.
== Interactions == Within the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase) complex, the encoded protein interacts with COA3 and SMIM20/MITRAC7. This interaction with SMIM20 stabilizes the newly synthesized MT-CO1 and prevents its premature turnover.<ref>{{cite journal | vauthors = Dennerlein S, Oeljeklaus S, Jans D, Hellwig C, Bareth B, Jakobs S, Deckers M, Warscheid B, Rehling P | display-authors = 6 | title = MITRAC7 Acts as a COX1-Specific Chaperone and Reveals a Checkpoint during Cytochrome c Oxidase Assembly | journal = Cell Reports | volume = 12 | issue = 10 | pages = 1644–1655 | date = September 2015 | pmid = 26321642 | doi = 10.1016/j.celrep.2015.08.009 | doi-access = free | hdl = 11858/00-001M-0000-0028-466E-C | hdl-access = free }}</ref> Additionally, it interacts with TMEM177 in a COX20-dependent manner.<ref>{{cite journal | vauthors = Lorenzi I, Oeljeklaus S, Aich A, Ronsör C, Callegari S, Dudek J, Warscheid B, Dennerlein S, Rehling P | display-authors = 6 | title = The mitochondrial TMEM177 associates with COX20 during COX2 biogenesis | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research| volume = 1865 | issue = 2 | pages = 323–333 | date = February 2018 | pmid = 29154948 | pmc = 5764226 | doi = 10.1016/j.bbamcr.2017.11.010 }}</ref><ref name=":0">{{Cite web|url=https://www.uniprot.org/uniprot/P00395|title=MT-CO1 - Cytochrome c oxidase subunit 1 - Homo sapiens (Human) - MT-CO1 gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-13}}{{CC-notice|cc=by4}}</ref><ref name=":3">{{cite journal | vauthors = | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158–D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }}</ref>
== References == {{reflist}}
===Additional sources=== {{InterPro content|IPR000883}} {{NLM content}}
== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ | title = Harvesting the fruit of the human mtDNA tree | journal = Trends in Genetics | volume = 22 | issue = 6 | pages = 339–345 | date = June 2006 | pmid = 16678300 | doi = 10.1016/j.tig.2006.04.001 }} * {{cite journal | vauthors = Bodenteich A, Mitchell LG, Polymeropoulos MH, Merril CR | title = Dinucleotide repeat in the human mitochondrial D-loop | journal = Human Molecular Genetics | volume = 1 | issue = 2 | pages = 140 | date = May 1992 | pmid = 1301157 | doi = 10.1093/hmg/1.2.140-a | doi-access = }} * {{cite journal | vauthors = Brown MD, Yang CC, Trounce I, Torroni A, Lott MT, Wallace DC | title = A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I | journal = American Journal of Human Genetics | volume = 51 | issue = 2 | pages = 378–385 | date = August 1992 | pmid = 1322638 | pmc = 1682694 }} * {{cite journal | vauthors = Lu X, Walker T, MacManus JP, Seligy VL | title = Differentiation of HT-29 human colonic adenocarcinoma cells correlates with increased expression of mitochondrial RNA: effects of trehalose on cell growth and maturation | journal = Cancer Research | volume = 52 | issue = 13 | pages = 3718–3725 | date = July 1992 | pmid = 1377597 }} * {{cite journal | vauthors = Marzuki S, Noer AS, Lertrit P, Thyagarajan D, Kapsa R, Utthanaphol P, Byrne E | title = Normal variants of human mitochondrial DNA and translation products: the building of a reference data base | journal = Human Genetics | volume = 88 | issue = 2 | pages = 139–145 | date = December 1991 | pmid = 1757091 | doi = 10.1007/bf00206061 | s2cid = 28048453 }} * {{cite journal | vauthors = Moraes CT, Andreetta F, Bonilla E, Shanske S, DiMauro S, Schon EA | title = Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region | journal = Molecular and Cellular Biology | volume = 11 | issue = 3 | pages = 1631–1637 | date = March 1991 | pmid = 1996112 | pmc = 369459 | doi = 10.1128/MCB.11.3.1631 }} * {{cite journal | vauthors = Attardi G, Chomyn A, Doolittle RF, Mariottini P, Ragan CI | title = Seven unidentified reading frames of human mitochondrial DNA encode subunits of the respiratory chain NADH dehydrogenase | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 51 Pt 1 | issue = 1 | pages = 103–114 | year = 1987 | pmid = 3472707 | doi = 10.1101/sqb.1986.051.01.013 }} * {{cite journal | vauthors = Chomyn A, Cleeter MW, Ragan CI, Riley M, Doolittle RF, Attardi G | title = URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit | journal = Science | volume = 234 | issue = 4776 | pages = 614–618 | date = October 1986 | pmid = 3764430 | doi = 10.1126/science.3764430 | bibcode = 1986Sci...234..614C }} * {{cite journal | vauthors = Chomyn A, Mariottini P, Cleeter MW, Ragan CI, Matsuno-Yagi A, Hatefi Y, Doolittle RF, Attardi G | display-authors = 6 | title = Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase | journal = Nature | volume = 314 | issue = 6012 | pages = 592–597 | year = 1985 | pmid = 3921850 | doi = 10.1038/314592a0 | s2cid = 32964006 | bibcode = 1985Natur.314..592C }} * {{cite journal | vauthors = Sanger F, Coulson AR, Barrell BG, Smith AJ, Roe BA | title = Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing | journal = Journal of Molecular Biology | volume = 143 | issue = 2 | pages = 161–178 | date = October 1980 | pmid = 6260957 | doi = 10.1016/0022-2836(80)90196-5 }} * {{cite journal | vauthors = Montoya J, Ojala D, Attardi G | title = Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs | journal = Nature | volume = 290 | issue = 5806 | pages = 465–470 | date = April 1981 | pmid = 7219535 | doi = 10.1038/290465a0 | s2cid = 4358928 | bibcode = 1981Natur.290..465M }} * {{cite journal | vauthors = Horai S, Hayasaka K, Kondo R, Tsugane K, Takahata N | title = Recent African origin of modern humans revealed by complete sequences of hominoid mitochondrial DNAs | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 2 | pages = 532–536 | date = January 1995 | pmid = 7530363 | pmc = 42775 | doi = 10.1073/pnas.92.2.532 | doi-access = free | bibcode = 1995PNAS...92..532H }} * {{cite journal | vauthors = Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N | title = Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA | journal = Nature Genetics | volume = 23 | issue = 2 | pages = 147 | date = October 1999 | pmid = 10508508 | doi = 10.1038/13779 | s2cid = 32212178 | doi-access = free }} * {{cite journal | vauthors = Ingman M, Kaessmann H, Pääbo S, Gyllensten U | title = Mitochondrial genome variation and the origin of modern humans | journal = Nature | volume = 408 | issue = 6813 | pages = 708–713 | date = December 2000 | pmid = 11130070 | doi = 10.1038/35047064 | s2cid = 52850476 | bibcode = 2000Natur.408..708I }} * {{cite journal | vauthors = Finnilä S, Lehtonen MS, Majamaa K | title = Phylogenetic network for European mtDNA | journal = American Journal of Human Genetics | volume = 68 | issue = 6 | pages = 1475–1484 | date = June 2001 | pmid = 11349229 | pmc = 1226134 | doi = 10.1086/320591 }} * {{cite journal | vauthors = Maca-Meyer N, González AM, Larruga JM, Flores C, Cabrera VM | title = Major genomic mitochondrial lineages delineate early human expansions | journal = BMC Genetics | volume = 2 | pages = 13 | year = 2003 | pmid = 11553319 | pmc = 55343 | doi = 10.1186/1471-2156-2-13 | doi-access = free }} {{refend}}
{{PDB Gallery|geneid=4512}} {{Mitochondrial enzymes}} {{Authority control}}
Category:Protein domains Category:Protein families Category:Transmembrane proteins Category:Human mitochondrial genes