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Identification of three transcription factors that bind a conserved responsive element of the COX4I2 gene, namely recombination signal sequence-binding protein Jkappa (RBPJ), coiled-coil-helix-coiled-coil-helix domain 2 (CHCHD2) and CXXC finger protein 5 (CXXC5).
Mutation analysis of COX4I2 is warranted in patients with malabsorption due to exocrine pancreatic insufficiency and in patients with dyserythropoeitic anemia.
COX4I2 is regulated by a novel oxygen sensitive promoter element (5'-GGACGTTCCCACG-3') conserved in mammals. Gene activity is maximal at 4% oxygen. Lung cytochrome c oxidase (COX) is 2.5 fold more active compared to liver COX, which lacks COX4I2.
COX4I2 is expressed in the highly oxygenated lung tissue. It is found in all cell types of the lung.
Cox4i2 is essential for acute but not chronic pulmonary oxygen sensing by triggering mitochondrial hyperpolarization.
Data (including data from cells of transgenic mouse embryos) suggest Hif1a (hypoxia inducible factor 1 alpha subunit) up-regulates transcription of heart/muscle isoform Cox7a1 under hypoxia; hypoxic induction of isoform Cox4i2 is HIF1a-independent.
propose a model in which reduced tissue ATP levels explain protection from airway hyperresponsiveness, i.e., absence of COX4i2 leads to reduced lung COX activity and ATP levels, which results in impaired airway constriction
the presence of the COX isoform IV-2 suppresses the sensitivity of COX to its allosteric regulator ATP and overrules the regulation of COX by the cellular energy level
Cytochrome c oxidase subunit IV is essential for assembly and respiratory function of the enzyme complex.
Under conditions of reduced oxygen availability, hypoxia-inducible factor 1 reciprocally regulates COX4 subunit expression by activating transcription of the genes encoding COX4-2 and LON, a mitochondrial protease that is required for COX4-1 degradation.
Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes isoform 2 of subunit IV. Isoform 1 of subunit IV is encoded by a different gene, however, the two genes show a similar structural organization. Subunit IV is the largest nuclear encoded subunit which plays a pivotal role in COX regulation.
, cytochrome c oxidase subunit 4 isoform 2, mitochondrial
, cytochrome c oxidase subunit IV-like 2
, Cox IV-2
, cytochrome c oxidase, subunit IVb
, cytochrome c oxidase, subunit 4b