Cytochrome c oxidase subunit III explained

Cytochrome c oxidase subunit III (COX3) is an enzyme that in humans is encoded by the MT-CO3 gene.^[1] It is one of main transmembrane subunits of cytochrome c oxidase. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits (MT-CO1, MT-CO2, MT-CO3) 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 .^{[2] [3]}

Structure

The MT-CO3 gene produces a 30 kDa protein composed of 261 amino acids.^{[4] [5]} COX3, the protein encoded by this gene, is a member of the cytochrome c oxidase subunit 3 family. This protein is located on the inner mitochondrial membrane. COX3 is a multi-pass transmembrane protein: in human, it contains 7 transmembrane domains at positions 15–35, 42–59, 81–101, 127–147, 159–179, 197–217, and 239–259.

Function

Cytochrome c oxidase is the terminal enzyme of the respiratory chain of mitochondria and many aerobic bacteria. It catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen:

4 cytochrome c⁺² + 4 H⁺ + O₂

\rightleftharpoons 4 cytochrome c⁺³ + 2 H₂O

This reaction is coupled to the pumping of four additional protons across the mitochondrial or bacterial membrane.^{[6] [7]}

Cytochrome c oxidase is an oligomeric enzymatic complex that is located in the mitochondrial inner membrane of eukaryotes and in the plasma membrane of aerobic prokaryotes. The core structure of prokaryotic and eukaryotic cytochrome c oxidase contains three common subunits, I, II and III. In prokaryotes, subunits I and III can be fused and a fourth subunit is sometimes found, whereas in eukaryotes there are a variable number of additional small subunits.^[8]

As the bacterial respiratory systems are branched, they have a number of distinct terminal oxidases, rather than the single cytochrome c oxidase present in the eukaryotic mitochondrial systems. Although the cytochrome o oxidases do not catalyze the cytochrome c but the quinol (ubiquinol) oxidation they belong to the same haem-copper oxidase superfamily as cytochrome c oxidases. Members of this family share sequence similarities in all three core subunits: subunit I is the most conserved subunit, whereas subunit II is the least conserved.^{[9] [10] [11]}

Clinical significance

Mutations in mtDNA-encoded cytochrome c oxidase subunit genes have been observed to be associated with isolated myopathy, severe encephalomyopathy, Leber hereditary optic neuropathy, mitochondrial complex IV deficiency, and recurrent myoglobinuria .^[12]

Leber hereditary optic neuropathy (LHON)

LHON is a maternally inherited disease resulting in acute or subacute loss of central vision, due to optic nerve dysfunction. Cardiac conduction defects and neurological defects have also been described in some patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes. Mutations at positions 9438 and 9804, which result in glycine-78 to serine and alanine-200 to threonine amino acid changes, have been associated with this disease.^[13]

Mitochondrial complex IV deficiency (MT-C4D)

Complex IV deficiency (COX deficiency) is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development, mental retardation, lactic acidemia, encephalopathy, ataxia, and cardiac arrhythmia. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death and a subset of patients manifest Leigh syndrome. The mutations G7970T and G9952A have been associated with this disease.^[14]

Recurrent myoglobinuria mitochondrial (RM-MT)

Recurrent myoglobinuria is characterized by recurrent attacks of rhabdomyolysis (necrosis or disintegration of skeletal muscle) associated with muscle pain and weakness, and followed by excretion of myoglobin in the urine. It has been associated with mitochondrial complex IV deficiency.^[15]

Subfamilies

• Cytochrome o ubiquinol oxidase, subunit III
• Cytochrome aa3 quinol oxidase, subunit III

Interactions

COX3 has been shown to have 15 binary protein-protein interactions including 8 co-complex interactions. COX3 appears to interact with SNCA, KRAS, RAC1, and HSPB2.^[16]

Further reading

• Moraes CT, Andreetta F, Bonilla E, Shanske S, DiMauro S, Schon EA . Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region . Molecular and Cellular Biology . 11 . 3 . 1631–7 . March 1991 . 1996112 . 369459 . 10.1128/MCB.11.3.1631.
• Chomyn A, Cleeter MW, Ragan CI, Riley M, Doolittle RF, Attardi G . URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit . Science . 234 . 4776 . 614–8 . October 1986 . 3764430 . 10.1126/science.3764430 . 1986Sci...234..614C .
• Chomyn A, Mariottini P, Cleeter MW, Ragan CI, Matsuno-Yagi A, Hatefi Y, Doolittle RF, Attardi G . Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase . Nature . 314 . 6012 . 592–7 . 1985 . 3921850 . 10.1038/314592a0 . 1985Natur.314..592C . 32964006 .
• Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG . Sequence and organization of the human mitochondrial genome . Nature . 290 . 5806 . 457–65 . April 1981 . 7219534 . 10.1038/290457a0 . 1981Natur.290..457A . 4355527 .
• Montoya J, Ojala D, Attardi G . Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs . Nature . 290 . 5806 . 465–70 . April 1981 . 7219535 . 10.1038/290465a0 . 1981Natur.290..465M . 4358928 .
• Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N . Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA . Nature Genetics . 23 . 2 . 147 . October 1999 . 10508508 . 10.1038/13779 . 32212178 . free .
• Ingman M, Kaessmann H, Pääbo S, Gyllensten U . Mitochondrial genome variation and the origin of modern humans . Nature . 408 . 6813 . 708–13 . December 2000 . 11130070 . 10.1038/35047064 . 2000Natur.408..708I . 52850476 .
• Maca-Meyer N, González AM, Larruga JM, Flores C, Cabrera VM . Major genomic mitochondrial lineages delineate early human expansions . BMC Genetics . 2 . 13 . 2003 . 1 . 11553319 . 55343 . 10.1186/1471-2156-2-13 . free .
• Herrnstadt C, Elson JL, Fahy E, Preston G, Turnbull DM, Anderson C, Ghosh SS, Olefsky JM, Beal MF, Davis RE, Howell N . Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups . American Journal of Human Genetics . 70 . 5 . 1152–71 . May 2002 . 11938495 . 447592 . 10.1086/339933 .
• Silva WA, Bonatto SL, Holanda AJ, Ribeiro-Dos-Santos AK, Paixão BM, Goldman GH, Abe-Sandes K, Rodriguez-Delfin L, Barbosa M, Paçó-Larson ML, Petzl-Erler ML, Valente V, Santos SE, Zago MA . Mitochondrial genome diversity of Native Americans supports a single early entry of founder populations into America . American Journal of Human Genetics . 71 . 1 . 187–92 . July 2002 . 12022039 . 384978 . 10.1086/341358 .
• Elkon H, Don J, Melamed E, Ziv I, Shirvan A, Offen D . Mutant and wild-type alpha-synuclein interact with mitochondrial cytochrome C oxidase . Journal of Molecular Neuroscience . 18 . 3 . 229–38 . June 2002 . 12059041 . 10.1385/JMN:18:3:229 . 42265181 .
• Mishmar D, Ruiz-Pesini E, Golik P, Macaulay V, Clark AG, Hosseini S, Brandon M, Easley K, Chen E, Brown MD, Sukernik RI, Olckers A, Wallace DC . Natural selection shaped regional mtDNA variation in humans . Proceedings of the National Academy of Sciences of the United States of America . 100 . 1 . 171–6 . January 2003 . 12509511 . 140917 . 10.1073/pnas.0136972100 . 2003PNAS..100..171M . free .
• Ingman M, Gyllensten U . Mitochondrial genome variation and evolutionary history of Australian and New Guinean aborigines . Genome Research . 13 . 7 . 1600–6 . July 2003 . 12840039 . 403733 . 10.1101/gr.686603 .
• Kong QP, Yao YG, Sun C, Bandelt HJ, Zhu CL, Zhang YP . Phylogeny of east Asian mitochondrial DNA lineages inferred from complete sequences . American Journal of Human Genetics . 73 . 3 . 671–6 . September 2003 . 12870132 . 1180693 . 10.1086/377718 .
• Temperley RJ, Seneca SH, Tonska K, Bartnik E, Bindoff LA, Lightowlers RN, Chrzanowska-Lightowlers ZM . Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria . Human Molecular Genetics . 12 . 18 . 2341–8 . September 2003 . 12915481 . 10.1093/hmg/ddg238 . free .
• Maca-Meyer N, González AM, Pestano J, Flores C, Larruga JM, Cabrera VM . Mitochondrial DNA transit between West Asia and North Africa inferred from U6 phylogeography . BMC Genetics . 4 . 15 . October 2003 . 14563219 . 270091 . 10.1186/1471-2156-4-15 . free .
• Coble MD, Just RS, O'Callaghan JE, Letmanyi IH, Peterson CT, Irwin JA, Parsons TJ . Single nucleotide polymorphisms over the entire mtDNA genome that increase the power of forensic testing in Caucasians . International Journal of Legal Medicine . 118 . 3 . 137–46 . June 2004 . 14760490 . 10.1007/s00414-004-0427-6 . 8413730 .
• Palanichamy MG, Sun C, Agrawal S, Bandelt HJ, Kong QP, Khan F, Wang CY, Chaudhuri TK, Palla V, Zhang YP . Phylogeny of mitochondrial DNA macrohaplogroup N in India, based on complete sequencing: implications for the peopling of South Asia . American Journal of Human Genetics . 75 . 6 . 966–78 . December 2004 . 15467980 . 1182158 . 10.1086/425871 .
• Starikovskaya EB, Sukernik RI, Derbeneva OA, Volodko NV, Ruiz-Pesini E, Torroni A, Brown MD, Lott MT, Hosseini SH, Huoponen K, Wallace DC . Mitochondrial DNA diversity in indigenous populations of the southern extent of Siberia, and the origins of Native American haplogroups . Annals of Human Genetics . 69 . Pt 1 . 67–89 . January 2005 . 15638829 . 3905771 . 10.1046/j.1529-8817.2003.00127.x .
• Rajkumar R, Banerjee J, Gunturi HB, Trivedi R, Kashyap VK . Phylogeny and antiquity of M macrohaplogroup inferred from complete mt DNA sequence of Indian specific lineages . BMC Evolutionary Biology . 5 . 26 . April 2005 . 15804362 . 1079809 . 10.1186/1471-2148-5-26 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Mitochondrial DNA-Associated Leigh Syndrome and NARP

Notes and References

1. Web site: Entrez Gene: COX3 cytochrome c oxidase subunit III.
2. Web site: MT-CO3 - Cytochrome c oxidase subunit 3 - Homo sapiens (Human) - MT-CO3 gene & protein. www.uniprot.org. en. 2018-08-21.
3. UniProt: the universal protein knowledgebase . Nucleic Acids Research . 45 . D1 . D158–D169 . January 2017 . 27899622 . 5210571 . 10.1093/nar/gkw1099 .
4. Web site: Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information. Yao. Daniel. amino.heartproteome.org. 2018-08-21. https://web.archive.org/web/20180822014906/https://amino.heartproteome.org/web/protein/P00414. 2018-08-22. dead.
5. 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 . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
6. Michel H . Cytochrome c oxidase: catalytic cycle and mechanisms of proton pumping--a discussion . Biochemistry . 38 . 46 . 15129–40 . November 1999 . 10563795 . 10.1021/bi9910934 .
7. Belevich I, Verkhovsky MI, Wikström M . Proton-coupled electron transfer drives the proton pump of cytochrome c oxidase . Nature . 440 . 7085 . 829–32 . April 2006 . 16598262 . 10.1038/nature04619 . 2006Natur.440..829B . 4312050 .
8. Mather MW, Springer P, Hensel S, Buse G, Fee JA . Cytochrome oxidase genes from Thermus thermophilus. Nucleotide sequence of the fused gene and analysis of the deduced primary structures for subunits I and III of cytochrome caa3 . The Journal of Biological Chemistry . 268 . 8 . 5395–408 . March 1993 . 10.1016/S0021-9258(18)53335-4 . 8383670 . free .
9. Santana M, Kunst F, Hullo MF, Rapoport G, Danchin A, Glaser P . Molecular cloning, sequencing, and physiological characterization of the qox operon from Bacillus subtilis encoding the aa3-600 quinol oxidase . The Journal of Biological Chemistry . 267 . 15 . 10225–31 . May 1992 . 10.1016/S0021-9258(19)50007-2 . 1316894 . free .
10. Chepuri V, Lemieux L, Au DC, Gennis RB . The sequence of the cyo operon indicates substantial structural similarities between the cytochrome o ubiquinol oxidase of Escherichia coli and the aa3-type family of cytochrome c oxidases . The Journal of Biological Chemistry . 265 . 19 . 11185–92 . July 1990 . 10.1016/S0021-9258(19)38574-6 . 2162835 . free .
11. García-Horsman JA, Barquera B, Rumbley J, Ma J, Gennis RB . The superfamily of heme-copper respiratory oxidases . Journal of Bacteriology . 176 . 18 . 5587–600 . September 1994 . 8083153 . 196760 . 10.1128/jb.176.18.5587-5600.1994.
12. Horváth R, Schoser BG, Müller-Höcker J, Völpel M, Jaksch M, Lochmüller H . Mutations in mtDNA-encoded cytochrome c oxidase subunit genes causing isolated myopathy or severe encephalomyopathy . Neuromuscular Disorders . 15 . 12 . 851–7 . December 2005 . 16288875 . 10.1016/j.nmd.2005.09.005 . 11683931 .
13. Johns DR, Neufeld MJ . Cytochrome c oxidase mutations in Leber hereditary optic neuropathy . Biochemical and Biophysical Research Communications . 196 . 2 . 810–5 . October 1993 . 8240356 . 10.1006/bbrc.1993.2321 . free .
14. Hanna MG, Nelson IP, Rahman S, Lane RJ, Land J, Heales S, Cooper MJ, Schapira AH, Morgan-Hughes JA, Wood NW . Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA . American Journal of Human Genetics . 63 . 1 . 29–36 . July 1998 . 9634511 . 1377234 . 10.1086/301910 .
15. Keightley JA, Hoffbuhr KC, Burton MD, Salas VM, Johnston WS, Penn AM, Buist NR, Kennaway NG . A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria . Nature Genetics . 12 . 4 . 410–6 . April 1996 . 8630495 . 10.1038/ng0496-410 . 13314201 .
16. Web site: 2 binary interactions found for search term COX3 . IntAct Molecular Interaction Database . EMBL-EBI . 2018-08-21 .