Recombinant Human Cytochrome c oxidase subunit 2 (MT-CO2)
Description
Definition of Recombinant Human Cytochrome c Oxidase Subunit 2 (MT-CO2)
Recombinant Human Cytochrome c Oxidase Subunit 2 (MT-CO2), also known as COXII, CO2, or COII, is the second subunit of cytochrome c oxidase (Complex IV) . It is a protein in eukaryotes encoded by the MT-CO2 gene . Cytochrome c oxidase is a component of the mitochondrial respiratory chain that catalyzes the reduction of oxygen to water . MT-CO2 is one of three subunits responsible for forming the functional core of cytochrome c oxidase .
Function of MT-CO2
MT-CO2 plays an essential role in transferring electrons from cytochrome c to the bimetallic center of the catalytic subunit 1, utilizing its binuclear copper A center . It contains two adjacent transmembrane regions in its N-terminus, and the major part of the protein is exposed to the periplasmic or the mitochondrial intermembrane space . MT-CO2 provides the substrate-binding site and contains the binuclear copper A center, which is likely the primary acceptor in cytochrome c oxidase . Furthermore, MT-CO2 facilitates glutaminolysis and sustains tumor cell survival upon glucose deprivation .
3.1. Mitochondrial Complex IV Deficiency
Variants of MT-CO2 have been associated with mitochondrial Complex IV deficiency, a deficiency in an enzyme complex of the mitochondrial respiratory chain that catalyzes the oxidation of cytochrome c utilizing molecular oxygen . This deficiency is characterized by heterogeneous phenotypes ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs . Other clinical manifestations include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental disability, delayed motor development, and mental retardation . Mutations of MT-CO2 are also known to cause Leigh's disease, which may be caused by an abnormality or deficiency of cytochrome oxidase .
A wide range of symptoms have been found in patients with pathogenic mutations in the MT-CO2 gene with mitochondrial Complex IV deficiency . For example, a deletion mutation of a single nucleotide (7630delT) in the gene has been found to cause symptoms of reversible aphasia, right hemiparesis, hemianopsia, exercise intolerance, progressive mental impairment, and short stature . A patient with a nonsense mutation (7896G>A) of the gene resulted in phenotypes such as short stature, low weight, microcephaly, skin abnormalities, severe hypotonia, and normal reflexes . A novel heteroplasmic mutation (7587T>C), which altered the initiation codon of the MT-CO2 gene in patients, has shown clinical manifestations such as progressive gait ataxia, cognitive impairment, bilateral optic atrophy, pigmentary retinopathy, a decrease in color vision, and mild distal-muscle wasting .
3.2. Other Associations
Juvenile myopathy, encephalopathy, lactic acidosis, and stroke have also been associated with mutations in the MT-CO2 gene . Furthermore, elevated expression of MT-CO2 is associated with poor prognosis in lung cancer patients .
MT-CO2 and Tumor Cell Survival
Glucose deprivation upregulates the expression of MT-CO2, which facilitates glutaminolysis and sustains tumor cell survival . Mechanistically, glucose deprivation activates Ras signaling to enhance MT-CO2 transcription and inhibits IGF2BP3, an RNA-binding protein, to stabilize MT-CO2 mRNA . Elevated MT-CO2 increases flavin adenosine dinucleotide (FAD) levels in activating lysine-specific demethylase 1 (LSD1) to epigenetically upregulate JUN transcription, consequently promoting glutaminase-1 (GLS1) and glutaminolysis for tumor cell survival . MT-CO2 is indispensable for oncogenic Ras-induced glutaminolysis and tumor growth . Silencing of MT-CO2 leads to inhibition of GLS1 transcription via suppression of c-JUN expression .
5.1. Identifiers for Cytochrome c Oxidase Subunit 2
| Category | Identifier |
|---|---|
| Aliases | COX2, mitochondrially encoded cytochrome c oxidase II, COII, MTCO2, Cytochrome c oxidase subunit II, CO II |
| External IDs | OMIM: 516040; MGI: 102503; HomoloGene: 5017; GeneCards: COX2; OMA: COX2 - orthologs |
| Wikidata |
5.2. Cytochrome c Oxidase Subunit II, Transmembrane Domain
| Category | Identifier |
|---|---|
| Symbol | COX2_TM |
| Pfam | PF02790 |
| InterPro | IPR011759 |
| PROSITE | PDOC00075 |
| SCOP2 | 1occ / SCOPe / SUPFAM |
| TCDB | 3.D.4 |
| OPM superfamily | 4 |
| OPM protein | 1v55 |
5.3. Cytochrome C oxidase subunit II, periplasmic domain
| Category | Identifier |
|---|---|
| Symbol | COX2 |
| Pfam | PF00116 |
| InterPro | IPR002429 |
| CDD | cd13912 |
Product Specs
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Target Background
- Elevated COX-2 and ALOX5 expression in colorectal cancer (CRC) tissues correlates with poorer patient prognosis. miR-216a-3p directly binds to their 3'-UTRs, inversely regulating their protein levels and influencing CRC cell proliferation. PMID: 28786533
- MT-CO2 and MT-ND5 mutations are implicated in maternally inherited diabetes and deafness (MIDD). A Tunisian family with MIDD and retinopathy exhibited mutations in MT-CO2 (m.8241T>G - p. F219C) and MT-ND5 (m.13276G>A - p. M314V), potentially explaining the retinopathy. PMID: 27422531
- High COX-2 levels are associated with poor breast cancer prognosis, larger tumor size, and lymph node metastasis. PMID: 27999206
- XRCC5 promotes colon cancer growth by cooperating with p300 to regulate COX-2 expression, suggesting the XRCC5/p300/COX-2 pathway as a potential therapeutic target. PMID: 29049411
- 17-AAG's inhibitory effects on PGE2 levels in HT-29 colorectal cancer cells are mediated by modulating COX-2 and 15-PGDH expression. PMID: 27075590
- Sequencing analysis revealed 17 variants, mostly non-synonymous changes in conserved amino acid residues, predominantly in the MT-CO2 gene of MUTYH-associated polyposis patients (P < 0.0001), frequently including the m.7763G>A variant. PMID: 26138249
- COA6 associates with COX2, crucial for its maturation and complex IV biogenesis. COA6 interacts with the copper chaperone SCO1, suggesting its involvement in copper delivery for COX2. PMID: 26160915
- A novel pathogenic MTCO2 mutation (8249G>A) was identified in Tunisian patients with mitochondrial myopathy. PMID: 23841600
- Four asthenospermic patients exhibited a double novel mutation in the COXII gene (m.8021 G/A), absent in normospermic infertile men. PMID: 24931671
- A non-synonymous COII variation strongly correlated with poor survival in patients with cytogenetically normal acute myeloid leukemia. PMID: 23826975
- Protein modeling revealed loss-of-function mutations in ND6 and COX-II proteins in malignant versus benign tumors. PMID: 24061460
- COX-2 expression plays a key role in tongue cancer proliferation and metastasis. PMID: 21069476
- Novel COII mutations cause maternally inherited nonsyndromic hearing loss. PMID: 22241583
- The apoptotic index of pulmonary vascular endothelial cells negatively correlated with COXII expression in chronic obstructive pulmonary disease patients. PMID: 21092633
- Differential expression of this protein was observed in thalami from schizophrenia patients. PMID: 20471030
- COX-II is induced in HIV-infected apoptotic T-cells. PMID: 19771519
- Clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function in aging muscle. PMID: 12031622
- Mitochondria-encoded COXII expression is HRG-responsive, and ErbB2 expression levels determine HRG's diverse biological activities. PMID: 12115729
- The COII/tRNA(Lys) intergenic 9-bp deletion polymorphism is more frequent in patients with myoclonic epilepsy with ragged-red fibers or mitochondrial encephalomyopathy syndrome than in healthy subjects. PMID: 15965049
- Mutations in mtDNA-encoded cytochrome c oxidase subunit II genes cause isolated myopathy or severe encephalomyopathy. PMID: 16288875
- COX-2 gene DNA hypermethylation may be a potential prognostic marker in early-stage cervical cancer. PMID: 17578348
- SCO1 physically associates with the cytochrome c oxidase complex in human muscle mitochondria, suggesting a link between CcO and cellular copper homeostasis regulation. PMID: 19295170
- SCO2 acts upstream of SCO1 and is essential for CO II synthesis. PMID: 19336478
- CoxII is phosphorylated by EGFR and c-Src; EGF stimulation reduces Cox activity and cellular ATP, largely depending on mitochondria-localized EGFR. PMID: 19840943
- Observational study of gene-environment interaction and pharmacogenomic/toxicogenomic analysis. (HuGE Navigator) PMID: 12732844
Q&A
Basic Research Questions
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What is MT-CO2 and what is its role in cellular respiration?
MT-CO2 (also known as COX2, COII, or COXII) is one of the three mitochondrially-encoded subunits of cytochrome c oxidase (Complex IV), the terminal enzyme in the mitochondrial electron transport chain . This enzyme catalyzes the reduction of oxygen to water while simultaneously pumping protons across the inner mitochondrial membrane, contributing to the electrochemical gradient that drives ATP synthesis .
Functionally, MT-CO2 contains the critical dinuclear copper A center (CuA) that receives electrons from cytochrome c in the intermembrane space and transfers them to heme A of subunit 1 (MT-CO1), which then transfers them to the binuclear center formed by heme A3 and copper B where oxygen reduction occurs . This electron transfer pathway is essential for aerobic respiration and energy production.
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How is the MT-CO2 gene organized in the mitochondrial genome?
The MT-CO2 gene is located on the p arm of the mitochondrial DNA at position 12 and spans 683 base pairs in humans . The gene produces a 25.6 kDa protein composed of 227 amino acids . It is one of the three mitochondrial DNA (mtDNA) encoded subunits (MT-CO1, MT-CO2, MT-CO3) of respiratory complex IV, while the remaining subunits are encoded by nuclear genes .
The structure of MT-CO2 contains two transmembrane alpha-helices in its N-terminal domain . The gene contains important conserved regions, including a cysteine loop at positions 196 and 200 and a conserved histidine at position 204, which contribute to the formation of the copper A center critical for electron transfer .
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What methodologies are available for detecting and quantifying MT-CO2 in biological samples?
Several approaches are commonly used to detect and quantify MT-CO2:
ELISA (Enzyme-Linked Immunosorbent Assay):
Sandwich ELISA kits allow specific quantification of MT-CO2 in various samples including tissue homogenates, cell lysates, and biological fluids . These assays typically have sensitivity in the range of 0.053-0.119 ng/mL and detection ranges of approximately 0.16-20 ng/mL .ELISA Kit Properties Specifications Sensitivity 0.053-0.119 ng/mL Detection Range 0.16-20 ng/mL Sample Types Tissue homogenates, cell lysates, biological fluids Assay Duration ~3.5 hours Intra-assay Precision CV% < 8% Inter-assay Precision CV% < 10% Recovery Rate 87-99% (average: 93%) Immunohistochemistry (IHC):
Ready-to-use IHC kits enable visualization of MT-CO2 in fixed tissue samples, particularly useful for studying protein localization in tissues .COX Histochemistry:
This technique is particularly valuable for mapping regional brain metabolism in animals, exploiting the correlation between COX enzyme amount/activity and neuronal activity .Western Blotting:
Using antibodies specific to MT-CO2, Western blotting allows detection of the protein in various sample types and can reveal changes in expression levels or post-translational modifications . -
How is MT-CO2 inserted into the inner mitochondrial membrane and assembled into Complex IV?
MT-CO2 assembly into cytochrome c oxidase involves a complex process requiring multiple nuclear-encoded assembly factors . The assembly process includes:
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Translation of MT-CO2 mRNA: Requires specific translational activators that interact with the 5' untranslated regions of mitochondrial mRNA transcripts .
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Membrane insertion: The hydrophobic transmembrane domains are inserted into the inner mitochondrial membrane with the assistance of specialized chaperones .
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Cofactor incorporation: The copper A (CuA) center is incorporated into MT-CO2, requiring copper chaperones like SCO1 and SCO2 .
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Subunit association: MT-CO2 associates with MT-CO1 and other subunits in a specific order to form functional subcomplexes that eventually assemble into the complete cytochrome c oxidase complex .
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Homodimerization: The fully assembled complex forms a homodimer stabilized by cardiolipin, which is essential for enzymatic activity .
Mutations in assembly factors such as SURF1, SCO1, SCO2, COX10, COX15, COX20, COA5, and LRPPRC can disrupt this process, leading to various mitochondrial diseases .
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What experimental models are most appropriate for studying MT-CO2 function?
Several experimental models have proven valuable for MT-CO2 research:
Yeast (Saccharomyces cerevisiae):
Particularly useful for studying basic assembly mechanisms due to genetic tractability and high conservation of mitochondrial functions. The COX2 gene can be manipulated, and the effects on respiratory function can be readily assessed .Mammalian Cell Lines:
Human cell lines like A549 and H1299 have been used to study MT-CO2 functions in cancer metabolism through RNA interference (shRNA) approaches .Mouse Models:
Valuable for studying the physiological roles of MT-CO2 and mapping regional brain metabolism using COX histochemistry .Patient-Derived Cells:
Fibroblasts or muscle biopsies from patients with MT-CO2 mutations provide insights into pathological mechanisms .Bovine Heart Mitochondria:
Often used for structural studies of cytochrome c oxidase due to the abundance of mitochondria in heart tissue .The choice of model system depends on the specific research question, with yeast being preferred for mechanistic studies of assembly and human cell lines being more relevant for disease-related research.
