Alternative titles; symbols
HGNC Approved Gene Symbol: MT-CO1
SNOMEDCT: 58610003, 67434000; ICD10CM: H47.22;
Cytochrome c oxidase subunit I (CO1 or MTCO1) is 1 of 3 mitochondrial DNA (mtDNA) encoded subunits (MTCO1, MTCO2, MTCO3) of respiratory Complex IV. Complex IV is located within the mitochondrial inner membrane and is the third and final enzyme of the electron transport chain of mitochondrial oxidative phosphorylation. It collects electrons from reduced cytochrome c and transfers them to oxygen to give water. The energy released is used to transport protons across the mitochondrial inner membrane. Complex IV is composed of 13 polypeptides. Subunits I, II, and III (MTCO1, MTCO2, MTCO3) are encoded by mtDNA while subunits IV, Va, Vb, VIa, VIb, VIc, VIIa, VIIb, VIIc, and VIII are nuclear encoded (Kadenbach et al., 1983; Shoffner and Wallace, 1995). While the mammalian Complex IV has a complex structure, several prokaryotic enzyme systems have the same catalytic functions, but are much simpler. These systems have been amenable to cloning and in vitro mutagenesis permitting detailed structure-function studies. Two well-studied systems are the cytochrome aa3 (cytochrome c oxidase) of Rhodobacter sphaeroides and the cytochrome bo (ubiquinol oxidase) of Escherichia coli. The R. sphaeroides enzyme has 3 subunits that are homologous to the 3 mammalian mtDNA subunits. R. sphaeroides subunit I is 62.1 kD and 52% identical and 76% similar to beef heart MTCO1; subunit II is 32.9 kD and 39% identical and 63% similar to beef MTCO2, and subunit III is 30.1 kD and 49% identical and 71% similar to beef heart. The Soret maxred = 444.5 nm (bovine = 443 nm) and alpha-band maxred = 606 nm (bovine = 604 nm). The extinction coefficients are identical (Hosler et al., 1993). These and other studies (Capaldi, 1990) have generated the following functional outlines for this enzyme.
The cytochrome c oxidase family of enzymes have 4 redox centers, 2 hemes and 2 copper centers. In mitochondrial Complex IV, the 2 hemes are a and a3 and the 2 coppers are CuA and CuB. The 2 hemes and CuB are bound to subunit I. For R. sphaeroides subunit I and for mammalian MTCO1, there are 12 membrane-spanning alpha-helices (I to XII). Of these helices, heme a is located between helix II and X, ligated with the invariant histidines at amino acid 102 (MTCO1 88) of helix II and at 421 (MTCO1 378) of helix X. Helix X lies between heme a and heme a3, with heme a3 bound to the opposite side of helix X at invariant histidine at amino acid 419 (MTCO1 376). Heme a3 is a component of a binuclear center which includes CuB and where oxygen is reduced to water. CuB is thought to lie adjacent to the iron of heme a3 and to be ligated to helix VI through invariant histidine 284 (MTCO1 240) and to helix VII through invariant histidines 333 and 334 (MTCO1 290 and 291). Amino acids histidine 411 (MTCO1 368), aspartate 412 (369), threonine 413 (370), and tyrosine 414 (371) occur in the conserved loop between helices IX and X, lying close to hemes a and a3, and may be in the proximity of the CuA located in subunit II (Hosler et al., 1993).
Subunit II of Complex IV interacts with cytochrome c and contains the CuA center. This means that the pathway of electron transfer through Complex IV is from cytochrome c, to CuA, to cytochrome a, and then to the binuclear center of cytochrome a3-CuB. It is thought that the transfer of electrons from cytochrome a to the binuclear center is the key control point in the reaction and one of the major points of energy transduction (Hill, 1993).
Proton translocation in Complex IV involves four electrons to reduce O2 and four protons taken up from the matrix side of the mitochondrial membrane for the formation of H2O. Four more protons are vertically translocated from the matrix to the cytosol side of the membrane. Evidence is accumulating that proton translocation is linked to electron transfer at the binuclear oxygen (O2) binding site, which has been extended to suggest that proton translocation is associated with proximal ligand exchange between tyrosine and histidine on cytochrome a3 (Rousseau et al., 1993).
The toxicity of classical inhibitors of Complex IV is the result of drug interaction with these reactive sites. Cyanide and azide form a bridge between cytochrome a3 and CuB. Thiocyanate and formate bind elsewhere on the binuclear center, probably at CuB (Palmer, 1993).
Subunit III is an universal component of cytochrome c oxidase. Previously, it was thought to participate in proton translocation because dicyclohexylcarbodiimide (DCCD), a inhibitor of proton transport in other systems, binds to the glutamate at position 90 in subunit III (Prochaska et al., 1981). However, more recent studies place this function at the binuclear center in subunit I. Hence, the function of subunit III remains unclear.
The functions of the 10 nuclear encoded Complex IV subunits is just beginning to be elucidated. Three of the subunits, VIa, VIIa, and VIII, have two isoforms, one expressed in heart and skeletal muscle and the other in the remaining tissues (Capaldi, 1990; Lomax and Grossman, 1989). The differential expression of this genes is in part the product of differential transcription (Wallace, 1993).
MTCO1 is encoded by the guanine-rich heavy (H) strand of the mtDNA and located between nucleotide pairs (nps) 5904 and 7444 (Anderson et al., 1981; Wallace et al., 1994). It is maternally inherited along with the mtDNA (Giles et al., 1980; Case and Wallace, 1981).
The MTCO1 gene encompasses 1540 nps of continuous mtDNA which lacks introns and encodes a single polypeptide. The mRNA begins with a 12-np 5-prime nontranslated sequence, then the AUG start codon, the polypeptide coding sequence which ends in an AGA codon which serves as a stop codon, and the extends 72 nps through the antisense tRNAser(UCN) that serves as a 3-prime nontranslated region (Ojala et al., 1981; Attardi et al., 1982). The MTCO1 gene is transcribed as a part of the polycistronic H-strand transcript flanked by tRNAtyr at the 5-prime end and tRNAasp at the 3-prime end. Then these tRNAs are cleaved out of the transcript freeing transcript 9, the mRNA for MTCO1. The mRNA is then polyadenylated (Anderson et al., 1981; Ojala et al., 1981; Attardi et al., 1982).
The predicted molecular weight (MW) of MTCO1 is 57 kD (Anderson et al., 1981; Wallace et al., 1994). However, its apparent MW on SDS-polyacrylamide gels (PAGE) is somewhat less. Using Tris-glycine buffer it runs at 39.5 kD (Oliver et al., 1984; Oliver and Wallace, 1982; Wallace et al., 1986), whereas using urea-phosphate gives an apparent MW of 45 kD (Ching and Attardi, 1982; Hare et al., 1980).
Acin-Perez et al. (2003) identified a cell line containing single and double missense mutations in the cytochrome c oxidase (COX) subunit I gene of mouse mitochondrial DNA. When present in homoplasmy, the single mutant displayed a normal complex IV assembly but a significantly reduced COX activity, while the double mutant almost completely compensated the functional defect of the first mutation. The authors hypothesized that deleterious mutations can arise and become predominant; cultured cells can maintain several mtDNA haplotypes at stable frequencies; the respiratory chain has little spare COX capacity; and that the size of a cavity in the vicinity of val421 in MTCO1I of animal COX may affect the function of the enzyme.
Wisloff et al. (2005) hypothesized that artificial selection of rats based on low and high intrinsic exercise capacity would yield models that also contrast for cardiovascular disease risk. After 11 generations, rats with low aerobic capacity scored higher on cardiovascular risk factors that constitute the metabolic syndrome. The decrease in aerobic capacity was associated with decreases in the amounts of transcription factors required for mitochondrial biogenesis and in the amounts of oxidative enzymes in skeletal muscle. Wisloff et al. (2005) found that the amount of PPARG (601487), PPARG coactivator-1-alpha (PPARGC1A; 604517), ubiquinol-cytochrome c oxidoreductase core 2 subunit (UQCRC2; 191329), cytochrome c oxidase subunit I (MTCO1), uncoupling protein-2 (UCP2; 601693), and ATP synthase H(+)-transporting mitochondrial F1 complex (F1-ATP synthase; see 108729) were markedly reduced in the low capacity runner rats in comparison with the high capacity runners. The uniform decline in these proteins was consistent with the hypothesis that reduced aerobic metabolism plays a causal role in the development of the differences between the low capacity runner and high capacity runner rats. Wisloff et al. (2005) concluded that impairment of mitochondrial function may link reduced fitness to cardiovascular and metabolic disease.
Temperley et al. (2010) demonstrated that human mitoribosomes do invoke -1 frameshift at the AGA and AGG codons predicted to terminate the 2 ORFs in MTCO1 and MTND6 (516006), respectively. As a consequence, both ORFs terminate in the standard UAG codon, necessitating the use of only a single mitochondrial release factor.
By immunoblot analysis, Hayashi et al. (2015) showed that Higd1a (618623) expression was induced early in rat cardiomyocytes exposed to hypoxia. Immunoprecipitation analysis revealed that Higd1a directly associated with cytochrome c oxidase (CcO) and integrated into the CcO macromolecular complex, causing structural changes at heme a, the active center of CcO. Knockdown and overexpression analyses demonstrated that Higd1a positively regulated CcO activity and increased mitochondrial ATP production, thereby protecting cardiomyocytes against hypoxia.
Restriction site polymorphisms have been identified at the following nucleotide positions for the indicated enzymes (where '+' = site gain, '-' = site loss relative to the reference sequence, Anderson et al., 1981): Alu I: -5978, -5996, -6022, -6204, -6867, +7025, -7055; Ava II: +5984, +6332, +6581, +6699 (or 8719 or 8723); Dde I: -6296, +6356, -6377, -7103; Hae III: -6027, -6260, +6425, +6534, +6618, -6957, +7325, +7347; Hha I: -5971, +6166 or 6168; HinfI: -5983, -6211, +6610, -6871, -6931; Mbo I: -6904; Msp I: +6501, -6688, +7159; Pst I:-6910; Rsa I: +5985, +6915, -7013, +7241; Taq I: +6049 or 7854, -7335; Xba I: -7440 (Wallace et al., 1994).
One phenotypically relevant mutation localized to MTCO1 contributes to the etiology of Leber hereditary optic neuropathy (LHON; 535000) and is designated MTCO1*LHON7444A (516030.0001).
Davis et al. (1997) reported that 2 mitochondrial genes, the MTCO1 gene and the MTCO2 gene (516040), encoding CO subunits I and II, respectively, appeared to be associated with late-onset Alzheimer disease (see 502500); however, their work was later retracted. Prior to the retraction, Hirano et al. (1997) had noted that the DNA isolation method used by Davis et al. (1997) resulted in the coamplification of both authentic mtDNA-encoded COX genes and highly similar COX-like sequences embedded in nuclear DNA ('mtDNA pseudogenes'). Hirano et al. (1997) concluded that the observed heteroplasmy was an artifact. Wallace et al. (1997) had come to a similar conclusion. Using the same PCR primers utilized by Davis et al. (1997) to amplify CO1 and CO2 sequences from 2 independent mtDNA-less cell lines, they could amplify CO1 and CO2 sequences from both, demonstrating that these sequences are also present in the human nuclear DNA. Furthermore, they found all 5 of the mutations found by Davis et al. (1997) in addition to 32 single-base substitutions, including 2 in adjacent tRNAs, and a 2-bp deletion in the CO2 gene. Phylogenetic analysis of the nuclear CO1 and CO2 sequences revealed that they diverges from modern human mtDNAs early in the hominid evolution about 770,000 years before the present.
Deficiency of cytochrome c oxidase (COX) causes a clinically heterogeneous variety of neuromuscular and non-neuromuscular disorders in childhood and adulthood and theoretically can result from either nuclear or mitochondrial mutations with obvious differences in mode of inheritance (see 220110). Parfait et al. (1997) sequenced the 3 mitochondrially encoded COX subunits of complex IV to test for causative mutations in these genes. The study was performed in a series of 18 patients with isolated COX deficiency. They failed to detect any deleterious mutations in this series. Moreover, no mtDNA deletion was observed and sequencing of the flanking tRNA gene involved in the maturation of the COX transcripts failed to detect deleterious mutations as well. Their study supported the view that the disease-causing mutations do not lie in the mitochondrial genome but rather in the nuclear genes encoding either the COX subunits or the proteins involved in assembly of the complex. The results suggested further that a recurrence risk of 25% (as for an autosomal recessive mode of inheritance) can be used in genetic counseling of COX deficiencies.
Most mtDNA mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA changes would be expected to be severe. To determine the fate of the more severe mtDNA mutations, Fan et al. (2008) introduced mtDNAs containing 2 mutations that affect oxidative phosphorylation, one mild and one severe, into the female mouse germ line. The severe mutation, 13885insC, created a frameshift mutation in the ND6 gene (516006). When homoplasmic, this mutation inactivates oxidative phosphorylation complex I. The mild mutation was a missense mutation, T6589C, in the COI gene that converted the highly conserved valine at codon 421 to alanine (V421A). When homoplasmic, this mutation reduces the activity of oxidative phosphorylation complex IV by 50%. Fan et al. (2008) observed that the severe ND6 mutation was selectively eliminated during oogenesis within 4 generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, Fan et al. (2008) concluded that severe mitochondrial DNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness.
See 535000. This allele converts the AGA termination codon to a lysine codon (AAA), permitting extension of the MTCO1 polypeptide by 3 amino acids (lysine, glutamine, lysine) into the antisense tRNAser(UCN) sequence (Brown et al., 1992; Johns and Neufeld, 1993). The mutation is associated with an impaired mobility of the polypeptide on SDS-PAGE and a 36% reduction in Complex IV activity in patient lymphoblasts. Patients with this mutation cluster within the Caucasian mtDNA phylogenetic tree (Brown et al., 1992). However, the 2 cases that have been extensively studied also harbor other LHON mutations: the MTND1*LHON3460A mutation in one case and the MTND6*LHON14484A in the other. Hence, the MTCO1*LHON7444A mutation is probably a secondary LHON mutation (Brown and Wallace, 1994). In the 2 families that harbored this mutation, between 23 and 43% of the maternal relatives were affected with all the affected individuals being male (Brown, Lott and Wallace, unpublished data).
Pandya et al. (1999) reported 6 unrelated Mongolian deaf students with cosegregation of a 7444G-A mutation and a 1555A-G mutation in the MTRNR1 gene (561000.0001). Five of the individuals had a family history consistent with matrilineal transmission of hearing loss (500008). Only 2 individuals had a definite history of aminoglycoside exposure, but all 6 had severe to profound bilateral sensorineural hearing loss detected at birth or in infancy. Pandya et al. (1999) suggested that the 7444G-A mutation would share a common pathogenic mechanism as the adjacent 7445A-G mutation (590080.0002) in the MTTS1 gene, which results in aberrant processing of the tRNA-ser(UCN) precursor (see Guan et al., 1998).
Yuan et al. (2005) reported cosegregation of a homoplasmic 7444G-A mutation and a homoplasmic 1555A-G MTRNR1 mutation in a 3-generation Chinese family with aminoglycoside-induced sensorineural hearing loss (580000). One additional family member with both mutations, who had a history of exposure to noise but not to aminoglycoside, exhibited mild hearing impairment. The dosage and age at the time of drug administration seemed to be correlated with the severity of the hearing loss.
Mitochondrial iron overload in acquired idiopathic sideroblastic anemia (AISA) may be attributable to mutations of mitochondrial DNA because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron to ferrous iron. The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis. In 2 patients with AISA, Gattermann et al. (1997) identified point mutations of mtDNA affecting the same transmembrane helix within subunit I of cytochrome c oxidase. The mutations were detected by restriction fragment length polymorphism analysis and temperature gradient gel electrophoresis. The mutation in 1 patient was a T-to-C transition at nucleotide 6742, causing an amino acid change from methionine to threonine. The other patient had a T-to-C transition mutation at nucleotide 6721, changing isoleucine to threonine (see 516030.0003). Both amino acids are highly conserved in a wide range of species. Both mutations were heteroplasmic. They were present in bone marrow and whole blood samples, in isolated platelets, and in granulocytes, but appeared to be absent from T and B lymphocytes purified by immunomagnetic bead separation. They were not detected in either patient's buccal mucosa cells obtained by mouthwashes or in cultured skin fibroblasts derived from 1 of the patients. This pattern of involvement suggested that the mtDNA mutations in both patients occurred in a self-renewing bone marrow stem cell with myeloid determination. The identification of 2 point mutations with a very similar location suggested that cytochrome c oxidase plays an important role in the pathogenesis of AISA. Cytochrome c oxidase subunit I may be the physiologic site of iron reduction and transport through the inner mitochondrial membrane.
See 516030.0002 and Gattermann et al. (1997).
Jaksch et al. (1998) identified a G-to-A transition at nucleotide 6480 of the MTCO1 gene in a child, her mother, and sister with cytochrome c oxidase deficiency (220110) associated with sensorineural hearing loss, ataxia, myoclonic epilepsy, and mental retardation.
Early on, Warburg (1956) suggested that alterations of oxidative phosphorylation in tumor cells play a causative role in cancerous growth. Interest in the mitochondria with regard to neoplasia has revived, largely because of their role in apoptosis and other aspects of tumor biology. The mitochondrial genome is particularly susceptible to mutations because of the high level of reactive oxygen species (ROS) generated in this organelle, coupled with a low level of DNA repair. In a colorectal cancer (114500) cell line, Polyak et al. (1998) found a 6264G-A transition in the MTCO1 gene, resulting in truncation of the gene product as a result of a nonsense mutation changing gly121 to stop. The mitochondrial chromosome also contained insertion of an additional adenine after nucleotide 12418 in the lys28 codon of the MTND5 gene, resulting in frameshift.
In a young woman with a multisystem mitochondrial disorder and cytochrome c oxidase deficiency (220110), Bruno et al. (1999) identified a heteroplasmic G-to-A transition at nucleotide 6930 of the MTCO1 gene. The mutation changed a glycine codon to a stop codon, resulting in the predicted loss of the last 170 amino acids (33%) of the polypeptide. The mutation was present in the patient's muscle, myoblasts, and blood. It was not detected in mtDNA from leukocytes of the patient's mother, sister, and 4 maternal aunts. Bruno et al. (1999) studied the genetic, biochemical, and morphologic characteristics of trans-mitochondrial cybrid cell lines, obtained by fusing platelets from the patient with human cells lacking endogenous mtDNA. There was a direct relationship between the proportion of mutant mtDNA and the biochemical defect. They also observed that the threshold for the phenotypic expression of this mutation was lower than that reported in mutations involving tRNA genes. Bruno et al. (1999) suggested that this mutation causes a disruption in the assembly of the respiratory-chain complex IV.
Karadimas et al. (2000) identified a G-to-A substitution at mitochondrial nucleotide 5920 resulting in a trp-to-ter mutation in the MTCO1 gene. The mutation was identified only in COX-deficient skeletal muscle fibers from a 33-year-old man who suffered from recurrent myoglobinuria since childhood. Serum CPK levels ranged from 15,000 to 38,000. The mutation was heteroplasmic and abundantly present in COX-negative fibers but less abundant or absent in COX-positive fibers; it was not found in blood or fibroblasts from the patient or in blood samples from the patient's asymptomatic mother and sister. The sporadic occurrence of this mutation in muscle alone suggested that it arose de novo in myogenic stem cells after germ-layer differentiation.
Varlamov et al. (2002) identified a heteroplasmic 6489C-A missense mutation in the MTCO1 gene in a 17-year-old girl with epilepsia partialis continua. The point mutation led to a substitution of ile at the highly conserved leu196 (L196I). Muscle biopsy showed in single fibers decreased COX activity and lowered binding of COX antibodies, suggesting decreased stability of the mutated enzyme. Quantitative analysis of the mutation gene dosage effect on COX activity on single muscle fiber level revealed a very high threshold; a COX deficiency (see 220110) was observed only in fibers containing more than 95% mutant mtDNA. In apparent contrast to this high mutation gene dosage threshold, in vivo investigations of mitochondrial function in saponin-permeabilized muscle fibers containing approximately 90% mutated mtDNA showed decreased maximal rates of respiration and an increased sensitivity of fiber respiration to cyanide. This was due to a 2-fold increase of COX flux control on muscle fiber respiration and a 30% decrease of COX metabolic threshold, supporting the concept of tight COX control of oxidative phosphorylation in skeletal muscle.
In skeletal muscle tissue from a woman with COX deficiency (220110), Lucioli et al. (2006) identified a homoplasmic 6328C-T transition in the MTCO1 gene, resulting in a ser142-to-phe (S142F) substitution in the beginning of the fourth N-terminal transmembrane helix. Expression of the homologous mutation in the bacterium Paracoccus denitrificans resulted in a significant decrease in COX enzyme activity.
In colonocytes from cytochrome c oxidase-deficient crypts from a patient with colon cancer (114500), Greaves et al. (2006) identified a 6277A-G transition in the MTCO1 gene, predicted to result in a gly125-to-asp (G125D) substitution at a well-conserved residue.
Namslauer and Brzezinski (2009) used site-directed mutagenesis to alter the residue corresponding to gly125 in the MTCO1 gene of the bacterium Rhodobacter sphaeroides (G171D), and demonstrated that G171D-mutant COX displayed steady-state catalytic activity linked to proton pumping that was approximately 34% of wildtype. In addition, an intrinsic proton leak was found in the enzyme, which would lead to decreased overall energy-conversion efficiency of the respiratory chain, perturbing transport processes such as protein, ion, and metabolite trafficking.
In colonocytes from cytochrome c oxidase-deficient crypts from a patient with colon cancer (114500), Greaves et al. (2006) identified a 7275T-C transition in the MTCO1 gene, predicted to result in a ser458-to-pro (S458P) substitution.
Namslauer and Brzezinski (2009) used site-directed mutagenesis to alter the residue corresponding to ser458 in the MTCO1 gene of the bacterium Rhodobacter sphaeroides (A501P), and found that A501P-mutant COX was not expressed, indicating that the amino acid substitution results in a severely altered overall structure of the enzyme.
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