Alternative titles; symbols
HGNC Approved Gene Symbol: MT-CO3
SNOMEDCT: 58610003, 67434000; ICD10CM: H47.22;
Cytochrome c oxidase subunit III (COIII or MTCO3) 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 then to oxygen to give water. The energy released is 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 VI, 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 III is a highly conserved and ubiquitous subunit of Complex III, yet its function remains unclear. The subunit is an integral membrane protein and it binds dicyclohexylcarbodiimide (DCCD) at glutamate 90, suggesting that it might participate in proton translocation (Prochaska et al., 1981; Suzuki et al., 1988). However, more recent evidence implicates the binuclear center of MTCO1 in proton transport (Rousseau et al., 1993; Hosler et al., 1993).
MTCO3 is encoded by the guanine-rich heavy (H) strand of the mtDNA located between nucleotide pairs (nps) 9207 and 9990 (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 MTCO3 gene encompasses 783 nps of continuous mtDNA sequence, lacking introns and encoding a single polypeptide. The mRNA begins with the AUG start codon and ends with the U of the UAA stop codon. This transcript is transcribed as part of the H-strand polycistronic transcript, flanked by the MTATP6 gene on the 5-prime end and tRNA on the 3-prime end. Cleavage at tRNA , followed by polyadenylation completes the termination codon (Ojala et al., 1981).
Cleavage at the 5-prime end occurs between the two As of the MTATP6 termination codon ACA TA //A UG ACC (ThrTerMetThr) creating transcript 15, the MTCO3 mRNA (Montoya et al., 1981; Ojala et al., 1981; Attardi et al., 1982). This is the only instance in which 2 separate transcripts, transcript 14 for MTATP8-MTATP6 and transcript 15 for MTCO3, are not separated by a tRNA. Hence, they must be processed by a separate system. If the 14+15 transcript were not cleaved, then MTATP6 would be translated, but MTCO3 might not be translated since its initiation codon overlaps the MTATP6 termination codon. Since the ratio between MTATP6 and MTCO3 can vary between patient and control cell mitochondria, it is possible that the cleavage of transcript 14 + 15 provides a mechanism for modulating the biogenesis of the electron transport chain relative to the ATP synthase (Wallace et al., 1986).
The predicted molecular weight (MW) of MTCO3 is 30 kD (Anderson et al., 1981; Wallace et al., 1994). However, its apparent MW on SDS-polyacrylamide gels (PAGE) is 22.5 kD using Tris-glycine buffer (Oliver et al., 1984; Oliver and Wallace, 1982; Wallace et al., 1986), whereas it is 18 kD when using urea-phosphate buffer (Ching and Attardi, 1982; Hare et al., 1980).
Restriction site polymorphisms have been identified at the following nucleotide position for the indicated enzymes (where '+' = site gain, '-' = site loss relative to the reference sequence, Anderson et al., 1981): Alu I: +9299, +9504, -9644; Ava II: +9589; Dde I: -9272, -9500, -9641; Hae II: +9326; Hae III: +9209, +9253, -9266, -9294, -9342, +9386, -9553, +9714, -9953; Hha I: +9327, -9380; HinfI: +9683, -9753, +9820, +9859, +9984; Mbo I: +9942; Rsa I: +9429, -9746, +9926; Taq I: -9751 (Wallace et al., 1994).
Some allelic variants for MTCO3 are associated with Leber hereditary optic neuropathy (LHON; 535000): MTCO3*LHON9438A (516050.0001) and MTCO3*LHON9804A (516050.0002).
This allele changes the highly conserved glycine at amino acid 78 to a serine (G78S). It was found in 5 independent patients, was homoplasmic, and was absent in 400 disease and normal controls (Johns and Neufeld, 1993).
The role of the 9438 sequence variation was questioned when it was found to occur in apparently healthy African and Cuban persons (Howell, 1994). Johns et al. (1994) described this mutation in 2 Cubans presenting with optic and peripheral neuropathy. Oostra et al. (1995) screened blood samples from 49 LHON pedigrees and from 38 isolated LHON probands for the presence of a 9438 mutation. They found the 9438 mutation in 2 of the 28 LHON pedigrees in which they previously found the 11778 mutation (516003.0001). Both mutations were homoplasmic in the individuals tested. The 9438 mutation was found in none of the other LHON pedigrees--i.e., the 7 carrying the 3460 mutation (516000.0001), the 11 carrying the 11484 mutation (516006.0001), or the 3 carrying neither of these 2 mutations--nor in any of the isolated LHON probands. Most convincing arguments for the primary pathogenic importance of the 3460, 11778, and 14484 mutations are the apparent mutual exclusion in LHON pedigrees and the fact that these mutations have never been reported in normal controls. However, the 9438 mutation does not meet either of these criteria. Oostra et al. (1995) concluded that the 9438 mutation is neither primarily nor secondarily involved in the pathogenesis of LHON. In pedigrees that present this mutation in the absence of 1 of the 3 known primary mutations, it is reasonable, in their view, to assume the presence of another primary mutation, the location of which remains to be discovered.
This allele changes the highly conserved alanine at amino acid 200 to a threonine (A200T). It was present in 3 independent patients, was homoplasmic, and was not found in 400 disease and normal controls (Johns and Neufeld, 1993).
Keightley et al. (1996) reported what was considered to be the first case of isolated COX deficiency (220110) to be defined at the molecular level. Two episodes of muscle cramps and myoglobinuria, the first precipitated by a viral illness, the second by prolonged exercise, prompted their investigation of a previously normal 15-year-old white female. Both episodes were associated with decreased caloric intake. Later, 2 further episodes occurred during which creatine kinase levels rose to 17,000-44,000 I.U. (normal = less than 170 I.U.). Muscle histochemistry showed type 1 fiber predominance, many ragged-red fibers which stained heavily for succinate dehydrogenase (SDH) activity, and a high proportion (64%) of COX-negative fibers. On electron microscopy, scattered areas showed increased numbers of mitochondria, some enlarged and irregular, with disordered cristae. They identified a 15-bp microdeletion leading to loss of 5 amino acids, in a highly conserved region of the MTCO3 gene. Mutant DNA comprised 92% of mtDNA in muscle and 0.7% in leukocytes. Immunoblots and immunocytochemistry suggested a lack of assembly or instability of the complex. Microdissected muscle fibers showed significantly higher proportions of mutant mtDNA in COX-negative than in COX-positive fibers. The 15-bp deletion, which was an in-frame, removed 5 amino acids from the third hydrophobic domain of COX subunit III and included 2 highly conserved phenylalanine residues.
Hanna et al. (1998) identified the first point mutation in mitochondrial DNA creating a stop codon in association with a human disorder. A 36-year-old woman experienced episodes of encephalopathy accompanied by lactic acidemia and had exercise intolerance and proximal myopathy. Histochemical analysis showed that 90% of muscle fibers exhibited decreased or absent cytochrome c oxidase (COX) activity (220110). Biochemical studies confirmed a severe isolated reduction in COX activity. Muscle immunocytochemistry revealed a pattern suggestive of a primary mtDNA defect in the COX-deficient fibers and was consistent with either reduced stability or impaired assembly of the holoenzyme. Sequence analysis identified a novel heteroplasmic G-to-A point mutation at nucleotide 9952 in the patient's skeletal muscle, which was not detected in her leukocyte mtDNA or in that of 120 healthy controls or 60 additional patients with mitochondrial disease. This point mutation was located in the 3-prime end of the MTCO3 gene and was predicted to result in the loss of the last 13 amino acids of the highly conserved C-terminal region of this subunit. It was not detected in mtDNA extracted from leukocytes, skeletal muscle, or myoblasts of the patient's mother or her 2 sons, indicating that this mutation was not maternally transmitted. Single-fiber PCR studies provided direct evidence for an association between this point mutation and COX deficiency and indicated that the proportion of mutant mtDNA required to induce COX deficiency is lower than that reported for tRNA-gene point mutations. The 9952G-A transition resulted in conversion of the wildtype TGA codon for tryptophan into a TAA stop codon.
Tiranti et al. (2000) reported an 11-year-old girl with a negative family history and an apparently healthy younger brother. Since 4 years of age, she had developed progressive spastic paraparesis associated with ophthalmoparesis, moderate mental retardation, severe lactic acidosis, and Leigh-like lesions in the putamen. A profound, isolated defect of COX (220110) was found by histochemical and biochemical assays in skin and muscle. Sequence analysis of muscle mtDNA revealed a virtually homoplasmic frameshift mutation in the MTCO3 gene, due to the insertion of an extra C at nucleotide position 9537. Although the 9537insC did not impair transcription of MTCO3, no full-length COX subunit III protein was detected in mtDNA translation assays in vivo. Western blot analysis showed a reduction of specific crossreacting material and the accumulation of early-assembly intermediates of COX, whereas the fully assembled complex was absent. One of these intermediates had an electrophoretic mobility different from those seen in controls, suggesting the presence of a qualitative abnormality of COX assembly. Immunostaining with specific antibodies failed to detect the presence of several smaller subunits in the complex lacking COX subunit III, in spite of the demonstration that these subunits were present in the crude mitochondrial fraction of the patient's cultured fibroblasts. The authors proposed a role for COX subunit III in the incorporation and maintenance of smaller COX subunits within the complex.
In a patient presenting with a relatively mild, childhood onset, slowly progressive myopathy with exercise intolerance, lactic acidosis, delayed growth, and numerous ragged-red fibers, lipidosis, and severe cytochrome c oxidase deficiency (220110) in skeletal muscle, Horvath et al. (2002) identified a heteroplasmic 9379G-A transition in the MTCO3 gene, resulting in a trp58-to-ter (W58X) mutation. Absence of the mutation in leukocytes of the patient and in members of the family on the mother's side pointed to a sporadic origin. Immunohistochemistry showed a decreased steady state level of COX subunits II (516040) and III in skeletal muscle, whereas staining of the nuclear-encoded subunit IV (123864) was normal.
This deletion occurs at the junction between the MTATP6 (516060) and MTCO3 genes. See 516060.0007, Seneca et al. (1996), Temperley et al. (2003).
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