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Gene Review

MT-CYB  -  mitochondrially encoded cytochrome b

Homo sapiens

Synonyms: COB, CYTB, Complex III subunit 3, Complex III subunit III, Cytochrome b, ...
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Disease relevance of MT-CYB


Psychiatry related information on MT-CYB

  • We describe a novel mutation in the cytochrome b gene of mitochondrial DNA (A15579G) associated with a selective decrease of muscle complex III activity in a patient who, besides severe exercise intolerance, also has multisystem manifestations (deafness, mental retardation, retinitis pigmentosa, cataract, growth retardation, epilepsy) [5].

High impact information on MT-CYB

  • The complex has a cytochrome b core and a central quinone exchange cavity, defined by the two monomers that are very similar to those in the respiratory cytochrome bc1 complex [6].
  • RESULTS: We found a total of three different nonsense mutations (G15084A, G15168A, and G15723A), one missense mutation (G14846A), and a 24-bp deletion (from nucleotide 15498 to 15521) in the cytochrome b gene in the five patients [1].
  • Kinetoplastid RNA editing: in vitro formation of cytochrome b gRNA-mRNA chimeras from synthetic substrate RNAs [7].
  • Patients with chronic granulomatous disease whose functional defect was localized to the neutrophil membrane (classic X-linked cytochrome b-negative type and two other rare variants) had normal amounts of both cytosolic components [8].
  • In association with these functional changes, we observed an increase in cellular contents of phagocyte cytochrome b (a critical component of the superoxide-producing oxidase) and immunoreactive cytochrome b heavy chain (the product of the gene that is defective in X-linked chronic granulomatous disease) [9].

Chemical compound and disease context of MT-CYB


Biological context of MT-CYB


Anatomical context of MT-CYB


Associations of MT-CYB with chemical compounds

  • The substitution per site of ATP6, the proton conducting subunit of ATPsynthase, CYTB, the core subunit of ubiquinone oxidoreductase that participate in both electron and proton transport, and ND3, a subunit of NADH dehydrogenase, showed the strongest correlations with longevity [22].
  • Identification of a cytochrome b-type NAD(P)H oxidoreductase ubiquitously expressed in human cells [15].
  • A mitochondrial cytochrome b mutation but no mutations of nuclearly encoded subunits in ubiquinol cytochrome c reductase (complex III) deficiency [23].
  • Sequence analysis of the cytochrome b, which is the only mitochondrial DNA-encoded subunit of complex III, revealed a homoplasmic G15498A mutation, resulting in the substitution of a highly conserved amino acid (glycine 251 into an aspartic acid) [24].
  • Cytochrome b also contains the sites to which various inhibitors and quinone antagonists bind and, consequently, inhibit the oxidoreductase [25].

Physical interactions of MT-CYB

  • No mutation in the nuclearly encoded complex III subunits was observed, but a mutation in the cd2 helix of the mitochondrial (mt) cytochrome b gene was found to alter the conformation of the bc1 complex in one patient with severe hypertrophic cardiomyopathy [23].
  • A large scale domain movement involving the iron-sulfur protein subunit is required for electron transfer from cytochrome b-bound ubihydroquinone to cytochrome c1 of the cytochrome bc1 complex [26].
  • Activation of the NADPH oxidase of phagocytes in the cell-free system requires the association of several cytosolic components with membrane-bound cytochrome b [27].
  • Folding models suggest that the highly conserved histidine 217 of the cytochrome b subunit from the cytochrome bc1 complex is close to the quinone reductase (Qi) site [28].
  • In this study, the amino acid sequences of the large (cybL) and small (cybS) subunits of cytochrome b in human liver complex II were deduced from cDNAs isolated by homology probing with mixed primers for the polymerase chain reaction [29].

Enzymatic interactions of MT-CYB


Regulatory relationships of MT-CYB

  • It is concluded that cobalt stimulates a signal cascade with cytochrome b as receptor and H2O2 as second messenger for regulating erythropoietin production [32].
  • To correct for differences in mitochondrial content, levels of UCP2 and UCP3 mRNA were expressed relative to cytochrome-b, a marker of mitochondrial content [33].
  • Sequence differences in the tRNA-proline (tRNApro) end of the mitochondrial control-region of three species of Pacific butterflyfishes accumulated 33-43 times more rapidly than did changes within the mitochondrial cytochrome b gene (cytb) [34].

Other interactions of MT-CYB

  • Comparison of the kaks ratios for each mtDNA gene from the tropical, temperate, and arctic zones revealed that ATP6 was highly variable in the mtDNAs from the arctic zone, cytochrome b was particularly variable in the temperate zone, and cytochrome oxidase I was notably more variable in the tropics [35].
  • The recombinant b5+b5R protein can be reduced by NAD(P)H, generating spectrum typical of reduced cytochrome b with alpha, beta, and Soret peaks at 557, 527, and 425 nm, respectively [15].
  • CYC1 and RISP have lower levels of sequence divergence between populations than CYTB, but, again, sequence analysis gives no evidence for positive selection acting on them [36].
  • The 15257 mutation altered a highly conserved amino acid in an extramembrane domain of cytochrome b that is associated with the ligation of the low potential b566 heme and the 5244 mutation altered a strongly evolutionarily conserved region of the ND2 polypeptide [37].
  • One proband had a non-synonymous A14062G mutation in the ND5 gene and the other had a non-synonymous G15221A mutation in the cytochrome b gene and a T1391C mutation in the 12S ribosomal RNA gene, whose importance in disease expression remains to be clarified [38].

Analytical, diagnostic and therapeutic context of MT-CYB

  • CYTB displays dramatic divergence between populations, but sequence analysis shows no evidence for positive selection driving this divergence [36].
  • The comparison of inhibition titrations in combination with the analysis of the primary structures has enabled us to identify amino acid residues in cytochrome b that may be involved in the binding of the inhibitors and, by extrapolation, quinone/quinol [25].
  • Western blot analysis indicated that interferon treatment reduces the steady-state level of cytochrome b in murine L-929 cells [39].
  • Sequence alignment of cytochrome b of the cytochrome bc1 complex from various sources reveals that bacterial cytochrome b contain an extra fragment at the C terminus [40].
  • Inter- and intraspecific phylogenetic trees relating mtDNAs based on restriction maps, cytochrome b sequences obtained via PCR, and the two data sets combined were compared to one another statistically and were broadly similar except for the phylogenetic position of Pomatosomus halli [41].


  1. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. Andreu, A.L., Hanna, M.G., Reichmann, H., Bruno, C., Penn, A.S., Tanji, K., Pallotti, F., Iwata, S., Bonilla, E., Lach, B., Morgan-Hughes, J., DiMauro, S. N. Engl. J. Med. (1999) [Pubmed]
  2. Mitochondrial encephalomyopathy and complex III deficiency associated with a stop-codon mutation in the cytochrome b gene. Keightley, J.A., Anitori, R., Burton, M.D., Quan, F., Buist, N.R., Kennaway, N.G. Am. J. Hum. Genet. (2000) [Pubmed]
  3. Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy. Andreu, A.L., Bruno, C., Shanske, S., Shtilbans, A., Hirano, M., Krishna, S., Hayward, L., Systrom, D.S., Brown, R.H., DiMauro, S. Neurology (1998) [Pubmed]
  4. Functional characterization of novel mutations in the human cytochrome b gene. Legros, F., Chatzoglou, E., Frachon, P., Ogier De Baulny, H., Laforêt, P., Jardel, C., Godinot, C., Lombès, A. Eur. J. Hum. Genet. (2001) [Pubmed]
  5. Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene. Wibrand, F., Ravn, K., Schwartz, M., Rosenberg, T., Horn, N., Vissing, J. Ann. Neurol. (2001) [Pubmed]
  6. Transmembrane traffic in the cytochrome b6f complex. Cramer, W.A., Zhang, H., Yan, J., Kurisu, G., Smith, J.L. Annu. Rev. Biochem. (2006) [Pubmed]
  7. Kinetoplastid RNA editing: in vitro formation of cytochrome b gRNA-mRNA chimeras from synthetic substrate RNAs. Harris, M.E., Hajduk, S.L. Cell (1992) [Pubmed]
  8. Genetic variants of chronic granulomatous disease: prevalence of deficiencies of two cytosolic components of the NADPH oxidase system. Clark, R.A., Malech, H.L., Gallin, J.I., Nunoi, H., Volpp, B.D., Pearson, D.W., Nauseef, W.M., Curnutte, J.T. N. Engl. J. Med. (1989) [Pubmed]
  9. Partial correction of the phagocyte defect in patients with X-linked chronic granulomatous disease by subcutaneous interferon gamma. Ezekowitz, R.A., Dinauer, M.C., Jaffe, H.S., Orkin, S.H., Newburger, P.E. N. Engl. J. Med. (1988) [Pubmed]
  10. Isolation of the structural genes for the Rieske Fe-S protein, cytochrome b and cytochrome c1 all components of the ubiquinol: cytochrome c2 oxidoreductase complex of Rhodopseudomonas capsulata. Daldal, F., Davidson, E., Cheng, S. J. Mol. Biol. (1987) [Pubmed]
  11. The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Dinauer, M.C., Orkin, S.H., Brown, R., Jesaitis, A.J., Parkos, C.A. Nature (1987) [Pubmed]
  12. Reconstitution of defective respiratory burst activity with partially purified human neutrophil cytochrome B in two genetic forms of chronic granulomatous disease: possible role of Rap1A. Quinn, M.T., Curnutte, J.T., Parkos, C.A., Mullen, M.L., Scott, P.J., Erickson, R.W., Jesaitis, A.J. Blood (1992) [Pubmed]
  13. Reevaluation of cytochrome b and flavin adenine dinucleotide in neutrophils from patients with chronic granulomatous disease and description of a family with probable autosomal recessive inheritance of cytochrome b deficiency. Ohno, Y., Buescher, E.S., Roberts, R., Metcalf, J.A., Gallin, J.I. Blood (1986) [Pubmed]
  14. The NADPH-dependent O-.2-generating oxidase from human neutrophils. Gabig, T.G. J. Biol. Chem. (1983) [Pubmed]
  15. Identification of a cytochrome b-type NAD(P)H oxidoreductase ubiquitously expressed in human cells. Zhu, H., Qiu, H., Yoon, H.W., Huang, S., Bunn, H.F. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  16. Mammalian mitochondrial DNA evolution: a comparison of the cytochrome b and cytochrome c oxidase II genes. Honeycutt, R.L., Nedbal, M.A., Adkins, R.M., Janecek, L.L. J. Mol. Evol. (1995) [Pubmed]
  17. A missense mutation in the mitochondrial cytochrome b gene in a revisited case with histiocytoid cardiomyopathy. Andreu, A.L., Checcarelli, N., Iwata, S., Shanske, S., DiMauro, S. Pediatr. Res. (2000) [Pubmed]
  18. Sequences from 14 mitochondrial genes provide a well-supported phylogeny of the Charadriiform birds congruent with the nuclear RAG-1 tree. Paton, T.A., Baker, A.J. Mol. Phylogenet. Evol. (2006) [Pubmed]
  19. Primary structure and unique expression of the 22-kilodalton light chain of human neutrophil cytochrome b. Parkos, C.A., Dinauer, M.C., Walker, L.E., Allen, R.A., Jesaitis, A.J., Orkin, S.H. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  20. Accelerated evolution of cytochrome b in simian primates: adaptive evolution in concert with other mitochondrial proteins? Andrews, T.D., Jermiin, L.S., Easteal, S. J. Mol. Evol. (1998) [Pubmed]
  21. Augmentation of stimulated eosinophil degranulation by VLA-4 (CD49d)-mediated adhesion to fibronectin. Neeley, S.P., Hamann, K.J., Dowling, T.L., McAllister, K.T., White, S.R., Leff, A.R. Am. J. Respir. Cell Mol. Biol. (1994) [Pubmed]
  22. Longevity and the evolution of the mitochondrial DNA-coded proteins in mammals. Rottenberg, H. Mech. Ageing Dev. (2006) [Pubmed]
  23. A mitochondrial cytochrome b mutation but no mutations of nuclearly encoded subunits in ubiquinol cytochrome c reductase (complex III) deficiency. Valnot, I., Kassis, J., Chretien, D., de Lonlay, P., Parfait, B., Munnich, A., Kachaner, J., Rustin, P., Rötig, A. Hum. Genet. (1999) [Pubmed]
  24. The deleterious G15498A mutation in mitochondrial DNA-encoded cytochrome b may remain clinically silent in homoplasmic carriers. Haut, S., de Villemeur, T.B., Brivet, M., Guiochon-Mantel, A., Boutron, A., Rustin, P., Legrand, A., Slama, A. Eur. J. Hum. Genet. (2004) [Pubmed]
  25. Mitochondrial cytochrome b: evolution and structure of the protein. Esposti, M.D., De Vries, S., Crimi, M., Ghelli, A., Patarnello, T., Meyer, A. Biochim. Biophys. Acta (1993) [Pubmed]
  26. Uncovering the molecular mode of action of the antimalarial drug atovaquone using a bacterial system. Mather, M.W., Darrouzet, E., Valkova-Valchanova, M., Cooley, J.W., McIntosh, M.T., Daldal, F., Vaidya, A.B. J. Biol. Chem. (2005) [Pubmed]
  27. Reconstitution of neutrophil NADPH oxidase activity in the cell-free system by four components: p67-phox, p47-phox, p21rac1, and cytochrome b-245. Abo, A., Boyhan, A., West, I., Thrasher, A.J., Segal, A.W. J. Biol. Chem. (1992) [Pubmed]
  28. Requirement of histidine 217 for ubiquinone reductase activity (Qi site) in the cytochrome bc1 complex. Gray, K.A., Dutton, P.L., Daldal, F. Biochemistry (1994) [Pubmed]
  29. Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23. Hirawake, H., Taniwaki, M., Tamura, A., Kojima, S., Kita, K. Cytogenet. Cell Genet. (1997) [Pubmed]
  30. Multiphasic oxidation-reduction of cytochrome b in the succinate-cytochrome c reductase. Tsou, C.L., Tang, H.L., Wang, D.C., Jin, Y.Z. Biochim. Biophys. Acta (1982) [Pubmed]
  31. Purification of the solubilized NADPH:O2 oxidoreductase of human neutrophils. Isolation of its catalytically inactive cytochrome b and flavoprotein redox centers. Green, T.R., Pratt, K.L. J. Biol. Chem. (1988) [Pubmed]
  32. Effects of cobalt on haem proteins of erythropoietin-producing HepG2 cells in multicellular spheroid culture. Görlach, A., Fandrey, J., Holtermann, G., Acker, H. FEBS Lett. (1994) [Pubmed]
  33. Skeletal muscle UCP2 and UCP3 expression in trained and untrained male subjects. Schrauwen, P., Troost, F.J., Xia, J., Ravussin, E., Saris, W.H. Int. J. Obes. Relat. Metab. Disord. (1999) [Pubmed]
  34. Rapid rate of control-region evolution in Pacific butterflyfishes (Chaetodontidae). McMillan, W.O., Palumbi, S.R. J. Mol. Evol. (1997) [Pubmed]
  35. Natural selection shaped regional mtDNA variation in humans. Mishmar, D., Ruiz-Pesini, E., Golik, P., Macaulay, V., Clark, A.G., Hosseini, S., Brandon, M., Easley, K., Chen, E., Brown, M.D., Sukernik, R.I., Olckers, A., Wallace, D.C. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  36. Evolution of interacting proteins in the mitochondrial electron transport system in a marine copepod. Willett, C.S., Burton, R.S. Mol. Biol. Evol. (2004) [Pubmed]
  37. Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy. Brown, M.D., Voljavec, A.S., Lott, M.T., Torroni, A., Yang, C.C., Wallace, D.C. Genetics (1992) [Pubmed]
  38. Atypical muscle pathology and a survey of cis-mutations in deaf patients harboring a 1555 A-to-G point mutation in the mitochondrial ribosomal RNA gene. Yamasoba, T., Goto, Y., Oka, Y., Nishino, I., Tsukuda, K., Nonaka, I. Neuromuscul. Disord. (2002) [Pubmed]
  39. Inhibition of mitochondrial function by interferon. Lewis, J.A., Huq, A., Najarro, P. J. Biol. Chem. (1996) [Pubmed]
  40. The role of extra fragment at the C-terminal of cytochrome b (Residues 421-445) in the cytochrome bc1 complex from Rhodobacter sphaeroides. Liu, X., Yu, C.A., Yu, L. J. Biol. Chem. (2004) [Pubmed]
  41. Phylogenetically informative length polymorphism and sequence variability in mitochondrial DNA of Australian songbirds (Pomatostomus). Edwards, S.V., Wilson, A.C. Genetics (1990) [Pubmed]
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