COX4I2 is located on the q arm of chromosome 20 in position 11.21 and has 6 exons.[7] The COX4I2 gene produces a 20 kDa protein composed of 171 amino acids.[9][10] The protein encoded by COX4I2 belongs to the cytochrome c oxidase IV family. COX4I2 has a transit peptide domain and a disulfide bond amino acid modification.[11][12] A Glu138 residue, which corresponds to a Glu136 residue in COX4I1, is believed to be highly conserved and structurally important for the mitochondrial COX response to hypoxia.[8]
Function
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. The COX4I2 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. It is located on the inner mitochondrial membrane on the matrix side. Expression of COX4I2 is highest in the placenta and the lungs.[7][11][12] Additionally, the expression of COX4I2, along with COX4I1, may be regulated by oxygen levels, with reduced levels of oxygen leading to increased COX4I2 expression and COX4I1 degradation. This suggests a role for COX4I2 in the optimization of the electron transfer chain under different conditions.[13]
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^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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^Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL (April 2007). "HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells". Cell. 129 (1): 111–22. doi:10.1016/j.cell.2007.01.047. PMID17418790. S2CID2331820.
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^Lynch SR, Sherman D, Copeland RA (January 1992). "Cytochrome c binding affects the conformation of cytochrome a in cytochrome c oxidase". The Journal of Biological Chemistry. 267 (1): 298–302. PMID1309738.
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Papadopoulou LC, Tsiftsoglou AS (September 1996). "Effects of hemin on apoptosis, suppression of cytochrome c oxidase gene expression, and bone-marrow toxicity induced by doxorubicin (adriamycin)". Biochemical Pharmacology. 52 (5): 713–22. doi:10.1016/0006-2952(96)00349-8. PMID8765469.
Vizirianakis IS, Pappas IS, Tsiftsoglou AS (March 2002). "Differentiation-dependent repression of c-myc, B22, COX II and COX IV genes in murine erythroleukemia (MEL) cells". Biochemical Pharmacology. 63 (5): 1009–17. doi:10.1016/S0006-2952(01)00937-6. PMID11911854.