Disease relevance of MT-CYB

• CONCLUSIONS: The sporadic form of mitochondrial myopathy is associated with somatic mutations in the cytochrome b gene of mtDNA [1].
• METHODS: We sequenced the mtDNA cytochrome b gene in blood and muscle specimens from five patients with severe exercise intolerance, lactic acidosis in the resting state (in four patients), and biochemical evidence of complex III deficiency [1].
• Mitochondrial encephalomyopathy and complex III deficiency associated with a stop-codon mutation in the cytochrome b gene [2].
• Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy [3].
• We illustrate these pitfalls by the analysis of the cytochrome b gene of 21 patients affected with a mitochondrial disease [4].

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

• 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 [10].
• The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex [11].
• Neutrophil plasma membranes from patients with the X-linked and autosomal recessive forms of chronic granulomatous disease (CGD) that lack cytochrome b are incapable of generating superoxide anion (O2-) in vivo and in vitro [12].
• 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 [13].
• The neutrophil oxidase fraction from one of the chronic granulomatous disease patients had a cytochrome b component that was spectrally abnormal, but a normal content of flavin adenine dinucleotide [14].

Biological context of MT-CYB

• Cytochrome b-type NAD(P)H oxidoreductases are involved in many physiological processes, including iron uptake in yeast, the respiratory burst, and perhaps oxygen sensing in mammals [15].
• Mitochondrial cytochrome b mutations have been reported to have a homogenous phenotype of pure exercise intolerance [5].
• The evolution of two mitochondrial genes, cytochrome b and cytochrome c oxidase subunit II, was examined in several eutherian mammal orders, with special emphasis on the orders Artiodactyla and Rodentia [16].
• We describe a pathogenic mutation in the mitochondrial cytochrome b gene in a patient with a multisystem disorder presenting as histiocytoid cardiomyopathy in whom a defect of ubiquinol cytochrome c oxidoreductase of the electron transport chain had been documented biochemically [17].
• Unlike short mitochondrial sequences (such as Cytochrome b alone), longer sequences yield a well-supported phylogeny for shorebirds across various taxonomic levels [18].

Anatomical context of MT-CYB

• Primary structure and unique expression of the 22-kilodalton light chain of human neutrophil cytochrome b [19].
• Cytochrome b comprising 91-kDa and 22-kDa subunits is a critical component of the membrane-bound oxidase of phagocytes that generates superoxide [19].
• A patient with progressive exercise intolerance, proximal weakness, and complex III deficiency in skeletal muscle had a missense mutation in the cytochrome b gene of mitochondrial DNA (G15762A) [3].
• We propose that the evolutionary rate increase observed for cytochrome b and cytochrome c oxidase subunit II may underlie an episode of coadaptive evolution of these two proteins in the mitochondria of simian primates [20].
• Treatment of eosinophils with 10(-8) to 10(-6) M formylmethionylleucyl-phenylalanine (FMLP) + 5 micrograms/ml cytochalasin B (CYTB) caused a concentration-dependent increase in EPO release, which was augmented by preincubation of eosinophils for 120 min in FN-coated (10 micrograms/ml) styrene wells versus eosinophils preincubated in control wells [21].

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

• After the initial three phases as described previously, cytochrome b becomes oxidized before cytochrome c1 when the limited amount of added substrate is being used up [30].
• The resolved flavoprotein and cytochrome b appear unable to catalyze either NADH nor NADPH oxidase activities with O2, ferricyanide, or nitroblue tetrazolium salt serving as electron acceptors [31].

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].

References