Alternative titles; symbols
HGNC Approved Gene Symbol: MT-CO2
SNOMEDCT: 67434000;
Cytochrome c oxidase subunit II (COII or MTCO2) 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 ferrocytochrome c (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 the mtDNA while subunits IV, Va, Vb, VIa, VIb, VIc, VIIa, VIIb, VIIc, and VIII are nuclear encoded (Kadenbach et al., 1983; Capaldi, 1990; Shoffner and Wallace, 1995). Subunits VIa, VIIa, and VIII have systemic as well as heart-muscle isoforms (Capaldi, 1990; Lomax and Grossman, 1989).
Subunit II contains one redox center, CuA, and collects electrons from ferrocytochrome b. The electrons are then transferred to cytochrome a of subunit I and on to the cytochrome a3-CuB binuclear reaction center. CuA most likely resides in a loop containing conserved cysteines at amino acids 196 and 200 and a conserved histidine at 204, with the fourth ligand being histidine 161. Cytochrome c interacts with subunit II through the association of a ring of lysines around the heme edge of cytochrome c with carboxyls in subunit II, specifically glutamate 129, aspartate 132, and glutamate 198 (Hill, 1993; Capaldi, 1990).
The predicted molecular weight (MW) of MTCO2 is 25.5 kD (Anderson et al., 1981; Wallace et al., 1994). However, its apparent MW on SDS-polyacrylamide gels (PAGE) is 23.6 kD using Tris-glycine buffer (Oliver et al., 1984; Oliver and Wallace, 1982; Wallace et al., 1986), whereas it is 20 kD when using urea-phosphate buffer (Ching and Attardi, 1982; Hare et al., 1980).
MTCO2 is encoded by the guanine-rich heavy (H) strand of the mtDNA located between nucleotide pairs (nps) 7586 and 8294 (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 MTCO2 gene encompasses 708 nucleotide pairs (nps) of continuous mtDNA sequence, lacking introns, and encoding a single polypeptide. The mRNA begins with the AUG start codon, proceeds through the polypeptide sequence to a UAG stop codon, and continues on through a 25-np 3-prime nontranslated region. This transcript is transcribed as a part of the H-strand polycistronic transcript, flanked by tRNAAsp on the 5-prime end and tRNALys on the 3-prime end. Cleavage at the tRNAs releases transcript 16, the MTCO2 mRNA. The transcript is then polyadenylated (Ojala et al., 1981; Attardi et al., 1982; Wallace et al., 1994).
The 25-np 3-prime-nontranslated sequence (5-prime-CACCCCCTCTACCCCCTCTAGAGGG) contains 2 9-np repeats which are polymorphic in the world populations. One polymorphism involves the deletion of 1 repeat and is common in Asian, Polynesian and Native American mtDNAs. A second polymorphism involves additional Cs inserted within the runs of Cs (Cann and Wilson, 1983; Wrischnik et al., 1987; Hertzberg et al., 1989; Ballinger et al., 1992; Schurr et al., 1990; Torroni et al., 1992; Torroni et al., 1993).
Using a yeast 2-hybrid screen and pull-down assays, Li et al. (2005) found that nonstructural protein-10 (NSP10) of SARS coronavirus interacted with components of cellular mitochondria, including NADH4L (MTND4L; 516004) and cytochrome oxidase II. Human cells transfected with NSP10 showed altered NADH-cytochrome activity and depolarization of the inner mitochondrial membrane. Moreover, NSP10 appeared to amplify the cytopathic effect of infection with the coronavirus 229E strain.
Szklarczyk et al. (2013) demonstrated that COX20 (614698) associates with and interacts with MTCO2, but likely does not affect transcription or translation of MTCO2 or any other gene. COX20 appears to act in the early steps of complex IV assembly, before the incorporation of the MTCO2 subunit.
Using small interfering RNA and endonuclease-mediated gene knockout with HEK293 cells, Bourens et al. (2014) found that COX20 was required for COX2 stability. In the absence of COX20, mitochondria accumulated respiratory chain assembly intermediates and showed reduced respiratory capacity. Protein pull-down and immunoprecipitation analyses revealed that COX20 interacted directly with COX2, as well as with SCO1 (603644) and SCO2 (604272), metallochaperones involved in biosynthesis of the COX2 redox center. COX20 interacted with newly synthesized COX2, and COX2 was required for association of COX20 with SCO1 and SCO2. Bourens et al. (2014) hypothesized that COX20 stabilizes newly synthesized COX2 by facilitating its cotranslational insertion into the mitochondrial inner membrane and maintains association with COX2 during SCO1- and SCO2-dependent maturation of its redox center.
Both small insertions and deletions have been identified in the 25 nps that encode the 3-prime nontranslated region of the MTCO2 mRNA. A 9-np deletion of 1 repeat between nps 8271 and 8281 or 8280 and 8290 is common in Asians, Polynesians, and Native Americans (Ballinger et al., 1992; Cann and Wilson, 1983; Harihara et al., 1992; Hertzberg et al., 1989; Horai and Matsunaga, 1986; Passarino et al., 1993; Schurr et al., 1990; Shields et al., 1992; Torroni et al. (1992, 1993, 1994); Wallace and Torroni, 1992; Wrischnik et al., 1987) and 3 copies of the repeat has been described in a few Asians (Shields et al., 1992; Passarino et al., 1993). A duplication of 4 Cs at np 8277 is also found in certain Asian populations (Ballinger et al., 1992; Cann and Wilson, 1983; Wrischnik et al., 1987).
Restriction site polymorphisms have also 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: -7641, -8074, +8198; Ava II: +8249; Dde I: -7750; Hae III: +7607, +7792, -7853, +7979, +8148, +8165, -8250; Hha I: -7598, +7617, +7828; HincII: -7853, +7937; HinfI: +7672, +7970; Mbo I: +7570, -7658, -7859, +7933; Msp I: -8112, -8150; Rsa I: +7697, +7702, -7897, -7912, -8012, +8078, +8156; Taq I: -8005 (Wallace et al., 1994).
Davis et al. (1997) reported that 2 mitochondrial genes, the MTCO1 gene (516030) and the MTCO2 gene, 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) and Wallace et al. (1997) presented evidence that the missense mutations that Davis et al. (1997) thought were related to Alzheimer disease were in fact located in mtDNA pseudogenes that are embedded in the nuclear genome where they have been transferred as part of the extensive transfer of genetic material from the primitive bacterial form, that was the progenitor of the mitochondrion, to the nucleus.
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). In an attempt to determine the respective roles of mtDNA and nuclear DNA mutations in COX deficiency, Parfait et al. (1997) sequenced the 3 mitochondrially encoded COX subunits of complex IV. 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. This 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 rather than other modes of inheritance) can be used in genetic counseling of COX deficiencies. On the other hand, Clark et al. (1999) identified a mutation in the MTCO2 gene in a family with COX II deficiency; see 516040.0001.
In a family with cytochrome c oxidase (COX) deficiency (220110), Clark et al. (1999) identified a 7587T-C transition in the initiation codon of the MTCO2 gene, predicting a change from methionine to threonine. The index case was the mother, a 57-year-old woman of normal intellect with a 5-to-10-year history of fatigue and unsteadiness of gait. There was no clinical evidence of retinal disease, deafness, muscle weakness, or cardiac disease. Her 34-year-old son was severely affected. Although normal at birth and in early childhood, at age 5 years he developed progressive gait ataxia. This progressed so that he became wheelchair-bound by age 25 years. He was severely cognitively impaired. Clinical examination demonstrated bilateral optic atrophy, pigmentary retinopathy, a marked decrease in color vision, and mild distal muscle wasting. The mutation load was present at 67% in muscle from the index case and at 91% in muscle from the clinically affected son. Muscle biopsy samples revealed isolated COX deficiency and mitochondrial proliferation. Single-muscle-fiber analysis demonstrated that the 7587C copy was at much higher load in COX-negative fibers than in COX-positive fibers. After microphotometric enzyme analysis, the mutation was shown to cause a decrease in COX activity when the mutant load was greater than 55 to 65%. In fibroblasts from the affected son, which contained more than 95% mutant mtDNA, there was no detectable synthesis or any steady-state level of COX II.
Early on, Warburg (1956) suggested that alterations of oxidative phosphorylation in tumor cells play a causative role in cancerous growth. Interest in 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, Polyak et al. (1998) found 3 somatic mutations in the mitochondrial genome. One was an 8009G-A transition in the MTCO2 gene, causing a val142-to-met missense substitution. The other 2 occurred in the MTCYB gene; see 516020.0003 and 516020.0004.
In a 14-year-old boy with proximal myopathy and lactic acidosis, Rahman et al. (1999) found, on muscle histochemistry and mitochondrial respiratory-chain enzymology, a marked reduction in COX activity (220110). Immunohistochemistry and immunoblot analyses with COX subunit-specific monoclonal antibodies showed a pattern suggestive of a primary mtDNA defect, most likely involving subunit II of cytochrome c oxidase. Sequence analysis of mitochondrial DNA demonstrated a novel heteroplasmic T-to-A transversion at nucleotide 7671 in the MTCO2 gene. The mutation changed a methionine to a lysine residue in the middle of the first N-terminal membrane-spanning region of COX II. Based on these and other observations, the authors suggested that in the COX protein, a structural association of COX II with COX I is necessary to stabilize the binding of heme a3 to COX I.
In twin brothers, Wong et al. (2001) described severe lactic acidosis caused by cytochrome c oxidase deficiency (220110). The one in whom molecular studies were performed died at 12 days of age, following a course of apnea, bradycardia, and severe lactic acidosis. The twin brother died at 2 days of age, after a similar course. The mutation found in the MTCO2 gene, 8042delAT, produced a truncated protein that was 72 amino acids, shorter than the wildtype protein. The mutant protein, missing one third of the amino acid residues at the C terminal essential for hydrophilic interaction with cytochrome c, ligand binding to copper and magnesium ions, and the formation of proton water channels, apparently could not perform essential mitochondrial respiratory functions.
Campos et al. (2001) reported what they judged to be the first nonsense mutation in the MTCO2 gene. The 3-year-old proposita was normal at birth but had psychomotor delay and failure to thrive after age 3 months. In addition to early-onset hypotonia, there was mild hypertrophic cardiomyopathy and pigmentary retinopathy, and COX deficiency in muscle (220110). A 7896G-A nonsense mutation was found, predicted to cause premature termination of the translation, with loss of 123 amino acids at the C terminus of COX II. The mutation was heteroplasmic in muscle, blood, and fibroblasts of the patient.
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