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Gene Review

COX5A  -  cytochrome c oxidase subunit Va

Homo sapiens

Synonyms: COX, COX-VA, Cytochrome c oxidase polypeptide Va, Cytochrome c oxidase subunit 5A, mitochondrial, VA
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Disease relevance of COX5A

  • Loss-of-function mutations of SURF1 cause Leigh syndrome associated with an isolated and generalized COX deficiency in humans [1].
  • Since ATRA also up-regulated COX-2 expression in SH-SY5Y human neuroblastoma cells, the current study was undertaken to analyze in these cells the mechanism through which ATRA increases COX activity [2].
  • We conclude that nuclear accumulation of COX-2 can be induced by resveratrol and that the COX has a novel intranuclear colocalization with Ser(15)-phosphorylated p53 and p300, which facilitates apoptosis in resveratrol-treated breast cancer cells [3].
  • ABSTRACT: BACKGROUND: Our recent results show that all-trans retinoic acid (ATRA), an active metabolite of vitamin A, induces COX-dependent hyperalgesia and allodynia in rats [2].
  • These data suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease [4].

Psychiatry related information on COX5A

  • We detected two distinct tRNA(Ser)(UCN) mutations, which have been recently described in single kindreds, in a subgroup of four patients with COX deficiency, deafness, myoclonic epilepsy, ataxia, and mental retardation [5].
  • An awareness of the existence of two COX isoforms has led to potential novel insights into disease pathogenesis (arthritis, Alzheimer's disease, cancer) and the regulation of normal physiology (brain, kidney) [6].
  • The therapeutic effect of celecoxib on the psychopathology of schizophrenia is speculated to be based on COX activity inhibition; however, the detailed pharmacological mechanisms are unclear [7].
  • This article investigated the time response of COX II induction by traction of the cauda equina assessed by a quantified RT-PCR method [8].
  • 1. Electrical stimulation of the baroceptive fibres of the vago-aortic trunks (VA St) reflexly induces, in the Ecéphale isolé (EI) cat preparation, a complete sleep cycle characterized by a progression of all stages of sleep previously described in chronic preparations (slow wave sleep, phasic slow wave sleep, paradoxical or REM sleep) [9].

High impact information on COX5A

  • The fraction of mtDNA deletions is significantly higher in cytochrome c oxidase (COX)-deficient neurons than in COX-positive neurons, suggesting that mtDNA deletions may be directly responsible for impaired cellular respiration [10].
  • The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome [11].
  • Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits [11].
  • Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane [11].
  • Leigh Syndrome (LS) is a severe neurological disorder characterized by bilaterally symmetrical necrotic lesions in subcortical brain regions that is commonly associated with systemic cytochrome c oxidase (COX) deficiency [4].

Chemical compound and disease context of COX5A


Biological context of COX5A

  • These results indicate a function for murine Surf1 protein (Surf1p) specifically related to COX and recapitulate, at least in part, the human phenotype [1].
  • Furthermore, PPARdelta activation or PGE(2) treatment induced the phosphorylation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha), a key enzyme that releases arachidonic acid (AA) substrate for PG production via COX [17].
  • Although the nucleotide sequences of all 13 genes are known, no mutation was found in nuclear-encoded subunit genes of COX-deficiency patients [18].
  • The biogenesis of the inner mitochondrial membrane enzyme cytochrome c oxidase (COX) is a complex process that requires the actions of ancillary proteins, collectively called assembly factors [19].
  • Most of these LS (COX-) patients show mutations in SURF1 on chromosome 9 (9q34), which encodes a protein essential for the assembly of the COX complex [20].

Anatomical context of COX5A

  • In conclusion our data indicate that S- and R-ibuprofen show similar antiproliferative effects in human colon carcinoma cell lines irrespective of its COX-inhibiting potencies [21].
  • The progressive accumulation of mtDNA deletions causes COX deficiency in muscle fibers and results in the clinical phenotype [22].
  • In fibroblasts from one family member, which contained >95% mutated mtDNA, there was no detectable synthesis or any steady-state level of COX II [23].
  • Heme A content was reduced in mitochondria from patient muscle and fibroblasts in proportion to the reduction in COX enzyme activity and the amount of fully assembled enzyme [24].
  • T(R)(adapt) cells produce PGE(2) and suppress effector T cell responses in a manner that is reversed by COX inhibitors and PGE(2) receptor-specific antagonists [25].

Associations of COX5A with chemical compounds

  • The activation of carcinogenic aromatic and heterocyclic amines and benzo[a]pyrene-7,8-diol to intracellular electrophiles by prostaglandin H synthase (COX) is well documented for ovine sources of this enzyme [26].
  • In COX enzyme inhibitory assays, ferulic and caffeic acid esters significantly inhibited both COX-1 and COX-2 enzymes [27].
  • Biochemical analysis of the original cell lines and the transmitochondrial cybrids generated by transferring mitochondrial DNAs to a common nuclear background, indicate that cytochrome c oxidase (COX) activity, respiration, and growth in galactose are impaired by the m.6267G>A mutation [28].
  • These cells released PGE2 but not NO2-, consistent with the induction of COX but not NOS in the fibroblast [29].
  • Sodium salicylate was a weak inhibitor of both COX isoforms in intact cells and was inactive against COX in either broken cells or purified enzyme preparations [30].

Physical interactions of COX5A

  • In this review, we examine how the structures of COXs relate mechanistically to cyclooxygenase and peroxidase catalysis and how alternative fatty acid substrates bind within the COX active site [31].
  • VEGF has been shown to interact with COX-derived prostaglandins in angiogenesis [32].

Regulatory relationships of COX5A

  • Aromatase levels in breast cancer cells are enhanced by prostaglandins and reduced by COX inhibitors [33].
  • Moreover, a non-selective COX inhibitor indomethacin also suppressed the expression of MMP-2 [34].
  • Taken together, these results provide the first evidence that COX inhibitors enhance chemosensitivity in neuroblastoma via downregulating HDM2 and augmenting p53 stability and nuclear accumulation.Oncogene (2007) 26, 1920-1931. doi:10.1038/sj.onc.1209981; published online 18 September 2006 [35].
  • The observed effects on endothelial cells appear to be COX-independent since both drugs selectively inhibited COX-2-activity and the applied concentrations lay beyond the IC(50) for inhibition of prostacyclin production [36].
  • These results indicate that loss of beta-catenin protein induced by sulindac metabolites is COX independent and at least partially due to reactivation of beta-catenin proteasome degradation and partially a result of caspase activation during the process of apoptosis [37].

Other interactions of COX5A

  • Mutations in the homologous human gene (SURF1) have been reported to cause Leigh's syndrome, a neurological disease associated with COX deficiency [38].
  • However, concerning inflammation-related targets, one should not limit the interest to COX and PLA2 enzymes [39].
  • Some of these rate accelerations (e.g. in COX5A and COX7C) are so pronounced that non-human mammalian sequences are more similar to sequences from Xenopus or zebrafish than they are to human [40].
  • (.)NO and PGE(2) are inflammatory mediators derived from the inducible iNOS and COX enzymes and are potentially important pharmacological targets in OA [41].
  • NSAIDs defined by their COX inhibition should also be defined by their effect on 15-PGDH [42].

Analytical, diagnostic and therapeutic context of COX5A

  • COX expression and kinase activity were analyzed by western blot [2].
  • Non-steroidal antiinflammatory drugs (NSAIDs) like aspirin, which block COX activity, have demonstrated their antitumor effects in preclinical and clinical trials [43].
  • Finally, experiments based on blue native two-dimensional gel electrophoresis indicated that assembly of COX in Surf-1p null mutants is blocked at an early step, most likely before the incorporation of subunit II in the nascent intermediates composed of subunit I alone or subunit I plus subunit IV [44].
  • Western blot analysis, immunohistochemistry, and single-fiber polymerase chain reaction demonstrated a tight correlation between COX defect, COX I expression, and percentage of mutation [45].
  • Rescue of the COX phenotype was observed in transfected cells from patients harboring SURF-1 mutations, but not in transfected cell lines from 2 patients in whom no mutations were detected by sequence analysis [46].


  1. Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice. Agostino, A., Invernizzi, F., Tiveron, C., Fagiolari, G., Prelle, A., Lamantea, E., Giavazzi, A., Battaglia, G., Tatangelo, L., Tiranti, V., Zeviani, M. Hum. Mol. Genet. (2003) [Pubmed]
  2. All-trans retinoic acid induces COX-2 and prostaglandin E2 synthesis in SH-SY5Y human neuroblastoma cells: involvement of retinoic acid receptors and extracellular-regulated kinase 1/2. Alique, M., Herrero, J.F., Lucio-Cazana, F.J. Journal of neuroinflammation (2007) [Pubmed]
  3. Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells. Tang, H.Y., Shih, A., Cao, H.J., Davis, F.B., Davis, P.J., Lin, H.Y. Mol. Cancer Ther. (2006) [Pubmed]
  4. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Zhu, Z., Yao, J., Johns, T., Fu, K., De Bie, I., Macmillan, C., Cuthbert, A.P., Newbold, R.F., Wang, J., Chevrette, M., Brown, G.K., Brown, R.M., Shoubridge, E.A. Nat. Genet. (1998) [Pubmed]
  5. A systematic mutation screen of 10 nuclear and 25 mitochondrial candidate genes in 21 patients with cytochrome c oxidase (COX) deficiency shows tRNA(Ser)(UCN) mutations in a subgroup with syndromal encephalopathy. Jaksch, M., Hofmann, S., Kleinle, S., Liechti-Gallati, S., Pongratz, D.E., Müller-Höcker, J., Jedele, K.B., Meitinger, T., Gerbitz, K.D. J. Med. Genet. (1998) [Pubmed]
  6. Selective cyclooxygenase-2 inhibitors. Golden, B.D., Abramson, S.B. Rheum. Dis. Clin. North Am. (1999) [Pubmed]
  7. Neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, in the hippocampus of patients with schizophrenia. Yokota, O., Terada, S., Ishihara, T., Nakashima, H., Kugo, A., Ujike, H., Tsuchiya, K., Ikeda, K., Saito, Y., Murayama, S., Ishizu, H., Kuroda, S. Prog. Neuropsychopharmacol. Biol. Psychiatry (2004) [Pubmed]
  8. INCREASES IN COX II mRNA IN THE RAT SPINAL CORD INDUCED BY CAUDA EQUINA TRACTION. Hirabayashi, K., Komagata, M., Yamada, J., Isshiki, A., Watanabe, Y. Int. J. Neurosci. (2006) [Pubmed]
  9. Characteristics of the experimental reflex sleep induced by vago-aortic nerve stimulation. Puizillout, J.J., Foutz, A.S. Electroencephalography and clinical neurophysiology. (1977) [Pubmed]
  10. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Kraytsberg, Y., Kudryavtseva, E., McKee, A.C., Geula, C., Kowall, N.W., Khrapko, K. Nat. Genet. (2006) [Pubmed]
  11. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Papadopoulou, L.C., Sue, C.M., Davidson, M.M., Tanji, K., Nishino, I., Sadlock, J.E., Krishna, S., Walker, W., Selby, J., Glerum, D.M., Coster, R.V., Lyon, G., Scalais, E., Lebel, R., Kaplan, P., Shanske, S., De Vivo, D.C., Bonilla, E., Hirano, M., DiMauro, S., Schon, E.A. Nat. Genet. (1999) [Pubmed]
  12. Induction of G0/G1 cell cycle arrest in ovarian carcinoma cells by the anti-inflammatory drug NS-398, but not by COX-2-specific RNA interference. Denkert, C., Fürstenberg, A., Daniel, P.T., Koch, I., Köbel, M., Weichert, W., Siegert, A., Hauptmann, S. Oncogene (2003) [Pubmed]
  13. Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells. Linnebank, M., Lutz, H., Jarre, E., Vielhaber, S., Noelker, C., Struys, E., Jakobs, C., Klockgether, T., Evert, B.O., Kunz, W.S., Wüllner, U. Neurobiol. Dis. (2006) [Pubmed]
  14. High response rate in the phase I/II study of meloxicam in juvenile rheumatoid arthritis. Foeldvari, I., Burgos-Vargas, R., Thon, A., Tuerck, D. J. Rheumatol. (2002) [Pubmed]
  15. Synthesis of interleukin 1beta, tumor necrosis factor-alpha, and interstitial collagenase (MMP-1) is eicosanoid dependent in human osteoarthritis synovial membrane explants: interactions with antiinflammatory cytokines. He, W., Pelletier, J.P., Martel-Pelletier, J., Laufer, S., Di Battista, J.A. J. Rheumatol. (2002) [Pubmed]
  16. COX-3 and the mechanism of action of paracetamol/acetaminophen. Botting, R., Ayoub, S.S. Prostaglandins Leukot. Essent. Fatty Acids (2005) [Pubmed]
  17. A Novel Positive Feedback Loop between Peroxisome Proliferator-activated Receptor-{delta} and Prostaglandin E2 Signaling Pathways for Human Cholangiocarcinoma Cell Growth. Xu, L., Han, C., Wu, T. J. Biol. Chem. (2006) [Pubmed]
  18. Two novel mutations of SURF1 in Leigh syndrome with cytochrome c oxidase deficiency. Teraoka, M., Yokoyama, Y., Ninomiya, S., Inoue, C., Yamashita, S., Seino, Y. Hum. Genet. (1999) [Pubmed]
  19. Defects in cytochrome oxidase assembly in humans: lessons from yeast. Zee, J.M., Glerum, D.M. Biochem. Cell Biol. (2006) [Pubmed]
  20. Maternal segmental disomy in Leigh syndrome with cytochrome c oxidase deficiency caused by homozygous SURF1 mutation. van Riesen, A.K., Antonicka, H., Ohlenbusch, A., Shoubridge, E.A., Wilichowski, E.K. Neuropediatrics. (2006) [Pubmed]
  21. Evidence of COX-2 independent induction of apoptosis and cell cycle block in human colon carcinoma cells after S- or R-ibuprofen treatment. Janssen, A., Maier, T.J., Schiffmann, S., Coste, O., Seegel, M., Geisslinger, G., Grösch, S. Eur. J. Pharmacol. (2006) [Pubmed]
  22. Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. Longley, M.J., Clark, S., Yu Wai Man, C., Hudson, G., Durham, S.E., Taylor, R.W., Nightingale, S., Turnbull, D.M., Copeland, W.C., Chinnery, P.F. Am. J. Hum. Genet. (2006) [Pubmed]
  23. An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy. Clark, K.M., Taylor, R.W., Johnson, M.A., Chinnery, P.F., Chrzanowska-Lightowlers, Z.M., Andrews, R.M., Nelson, I.P., Wood, N.W., Lamont, P.J., Hanna, M.G., Lightowlers, R.N., Turnbull, D.M. Am. J. Hum. Genet. (1999) [Pubmed]
  24. Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Antonicka, H., Leary, S.C., Guercin, G.H., Agar, J.N., Horvath, R., Kennaway, N.G., Harding, C.O., Jaksch, M., Shoubridge, E.A. Hum. Mol. Genet. (2003) [Pubmed]
  25. FOXP3+CD4+CD25+ adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism. Mahic, M., Yaqub, S., Johansson, C.C., Taskén, K., Aandahl, E.M. J. Immunol. (2006) [Pubmed]
  26. Carcinogen substrate specificity of human COX-1 and COX-2. Wiese, F.W., Thompson, P.A., Kadlubar, F.F. Carcinogenesis (2001) [Pubmed]
  27. Impact of alkyl esters of caffeic and ferulic acids on tumor cell proliferation, cyclooxygenase enzyme, and lipid peroxidation. Jayaprakasam, B., Vanisree, M., Zhang, Y., Dewitt, D.L., Nair, M.G. J. Agric. Food Chem. (2006) [Pubmed]
  28. m.6267G>A: a recurrent mutation in the human mitochondrial DNA that reduces cytochrome c oxidase activity and is associated with tumors. Gallardo, M.E., Moreno-Loshuertos, R., López, C., Casqueiro, M., Silva, J., Bonilla, F., Rodríguez de Córdoba, S., Enríquez, J.A. Hum. Mutat. (2006) [Pubmed]
  29. Nitric oxide activates cyclooxygenase enzymes. Salvemini, D., Misko, T.P., Masferrer, J.L., Seibert, K., Currie, M.G., Needleman, P. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  30. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Mitchell, J.A., Akarasereenont, P., Thiemermann, C., Flower, R.J., Vane, J.R. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  31. The structure of mammalian cyclooxygenases. Garavito, R.M., Mulichak, A.M. Annual review of biophysics and biomolecular structure. (2003) [Pubmed]
  32. Role of COX-2, VEGF and cyclin D1 in mammary infiltrating duct carcinoma. Lim, S.C. Oncol. Rep. (2003) [Pubmed]
  33. Novel sulfonanilide analogues suppress aromatase expression and activity in breast cancer cells independent of COX-2 inhibition. Su, B., Diaz-Cruz, E.S., Landini, S., Brueggemeier, R.W. J. Med. Chem. (2006) [Pubmed]
  34. Non-steroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 expression via repression of transcription in lung cancer cells. Pan, M.R., Chuang, L.Y., Hung, W.C. FEBS Lett. (2001) [Pubmed]
  35. Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma. Lau, L., Hansford, L.M., Cheng, L.S., Hang, M., Baruchel, S., Kaplan, D.R., Irwin, M.S. Oncogene (2007) [Pubmed]
  36. Effects of the selective COX-2 inhibitors celecoxib and rofecoxib on human vascular cells. Niederberger, E., Manderscheid, C., Grösch, S., Schmidt, H., Ehnert, C., Geisslinger, G. Biochem. Pharmacol. (2004) [Pubmed]
  37. Sulindac metabolites induce caspase- and proteasome-dependent degradation of beta-catenin protein in human colon cancer cells. Rice, P.L., Kelloff, J., Sullivan, H., Driggers, L.J., Beard, K.S., Kuwada, S., Piazza, G., Ahnen, D.J. Mol. Cancer Ther. (2003) [Pubmed]
  38. Shy1p is necessary for full expression of mitochondrial COX1 in the yeast model of Leigh's syndrome. Barrientos, A., Korr, D., Tzagoloff, A. EMBO J. (2002) [Pubmed]
  39. Chemistry and biology of anti-inflammatory marine natural products: molecules interfering with cyclooxygenase, NF-kappaB and other unidentified targets. Terracciano, S., Aquino, M., Rodriquez, M., Monti, M.C., Casapullo, A., Riccio, R., Gomez-Paloma, L. Current medicinal chemistry. (2006) [Pubmed]
  40. Amino acid replacement is rapid in primates for the mature polypeptides of COX subunits, but not for their targeting presequences. Schmidt, T.R., Goodman, M., Grossman, L.I. Gene (2002) [Pubmed]
  41. Dynamic compression counteracts IL-1beta induced iNOS and COX-2 activity by human chondrocytes cultured in agarose constructs. Chowdhury, T.T., Bader, D.L., Lee, D.A. Biorheology. (2006) [Pubmed]
  42. 15-Hydroxyprostaglandin-dehydrogenase is involved in anti-proliferative effect of non-steroidal anti-inflammatory drugs COX-1 inhibitors on a human medullary thyroid carcinoma cell line. Quidville, V., Segond, N., Lausson, S., Frenkian, M., Cohen, R., Jullienne, A. Prostaglandins Other Lipid Mediat. (2006) [Pubmed]
  43. COX-inhibitors relieve the immunosuppressive effect of tumor cells and improve functions of immune effectors. Lang, S., Picu, A., Hofmann, T., Andratschke, M., Mack, B., Moosmann, A., Gires, O., Tiwari, S., Zeidler, R. International journal of immunopathology and pharmacology. (2006) [Pubmed]
  44. Characterization of SURF-1 expression and Surf-1p function in normal and disease conditions. Tiranti, V., Galimberti, C., Nijtmans, L., Bovolenta, S., Perini, M.P., Zeviani, M. Hum. Mol. Genet. (1999) [Pubmed]
  45. Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease. Comi, G.P., Bordoni, A., Salani, S., Franceschina, L., Sciacco, M., Prelle, A., Fortunato, F., Zeviani, M., Napoli, L., Bresolin, N., Moggio, M., Ausenda, C.D., Taanman, J.W., Scarlato, G. Ann. Neurol. (1998) [Pubmed]
  46. Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency. Tiranti, V., Jaksch, M., Hofmann, S., Galimberti, C., Hoertnagel, K., Lulli, L., Freisinger, P., Bindoff, L., Gerbitz, K.D., Comi, G.P., Uziel, G., Zeviani, M., Meitinger, T. Ann. Neurol. (1999) [Pubmed]
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