Disease relevance of MT-CO3

• New mitochondrial DNA mutations were discovered in the cytochrome c oxidase subunit III gene in 8 independent Leber hereditary optic neuropathy probands [1].
• We have deleted the COIII gene from Paracoccus denitrificans [2].
• We have shown that expression levels of COXIII, a mitochondrial gene encoding one of the 13 subunits of cytochrome c oxidase, are abnormally low in colon tumors and colonic tissue at genetic risk for developing tumors but increase following in vitro treatment of HT29 human colonic adenocarcinoma cells with the fatty acid butyrate [3].
• A 15-base pair, in-frame, deletion (9480del15) in the mitochondrial DNA (mtDNA)-encoded cytochrome c oxidase subunit III (COX III) gene was identified previously in a patient with recurrent episodes of myoglobinuria and an isolated COX deficiency [4].
• In a panel of eight cloned complementary DNA sequences whose level of expression characterize colon cells as transformed in vivo and in vitro, one which may also serve as a marker of risk in familial polyposis and familial colon cancer flat mucosa has been identified as mitochondrial cytochrome c oxidase subunit 3 [5].

High impact information on MT-CO3

• COX-3: just another COX or the solitary elusive target of paracetamol [6]?
• Dicyclohexyl carbodiimide (DCCD) modifies a conserved glutamic acid residue in COIII and abolishes the proton translocation activity of the enzyme [7].
• COIII is one of the major subunits in the mitochondrial and a bacterial cytochrome c oxidase, cytochrome aa3 [2].
• The mutant phenotype can be complemented by introducing the COIII gene back to cells in a plasmid vector [2].
• This suggests that the region of base pairing between individual guide RNAs and the COIII transcript is not strictly conserved in kinetoplastids, implying gradual evolution of the editing process [8].

Biological context of MT-CO3

• One frameshift mutation, 9485delC, was in cytochrome c oxidase subunit III [9].
• However, phylogenetic analyses of cox3 amino acid and nucleotide sequences indicate that C. crispus COX3 is related to the green-plant mitochondrial lineage [10].
• Three were missense mutations (C14F, H186R, T173P) in NADH dehydrogenase subunit 2, and one was a frameshift mutation, 9485delC, in cytochrome c oxidase subunit III [11].
• Gene fragments or multiple copies of the cox3 and cob sequences may be abundant in the mitochondrial genome since Southern blots, using these sequences separately as probes, show multiple restriction fragments with several enzymes [12].
• Nucleotides as well as amino acid sequence variations of a COIII fragment were examined with parsimony and distance methods [13].

Anatomical context of MT-CO3

• We have identified a second DNA-binding protein in sea urchin embryo mitochondria, which interacts with a binding site in the major replication pause region, at the junction of the genes for ATP synthase subunit 6 and cytochrome c oxidase subunit III (COIII) [14].
• Steady-state levels of 12 S and 16 S mitochondrial (mt) rRNAs and four mRNAs (NADH dehydrogenase subunits 3 and 4/4L, cytochrome c oxidase subunit III, H(+)-ATPase subunits 6/6L) were estimated by hybridization of cellular RNA with cloned human mt DNA fragments during hypoxia of HeLa cells [15].
• The hamster cytochrome c oxidase mitochondrial subunit III (COIII) gene has been sequenced and identified as the gene upregulated in brain and skeletal muscle [16].

Associations of MT-CO3 with chemical compounds

• Two previously unreported amino acid replacements were detected in a third individual: amino acid 193 of cytochrome b was changed from alanine to threonine, and amino acid 88 of COIII was changed from threonine to alanine [17].
• Pre-edited COII mRNA was similarly cleaved adjacent to its small editing domain, while pre-edited COIII RNA was cleaved at multiple sites in the region where uridine addition and deletion occurs in vivo [18].
• COX-3, a variant of COX-1, has been found in canine brain and is inhibited by acetaminophen and dipyrone at physiological concentrations [19].
• Estrogen-nucleic acid adducts: guanine is major site for interaction between 3,4-estrone quinone and COIII gene [20].
• The observation that obstruction of in vitro replication of COIII template bound to 3,4-EQ suggests that estrogen quinone adducted lesions can arrest DNA polymerase [20].

Other interactions of MT-CO3

• Loss of these two residues removes the termination codon for MTATP6 and sets MTCO3 immediately in frame [21].
• In parallel, total RNA was extracted from samples of dissected heart and analyzed by Northern blot hybridization to determine the steady-state level of three RNA transcripts encoded by the COXII, COXIII, and COXIV genes [22].
• The mRNA levels for the mtDNA-encoded 12 S rRNA, ND2, ATPase6+8, COIII, ND5+6, and Cytb genes were also increased, whereas the mtDNA number declined [23].
• Three genes (COIII, NADH3 and NADH4) were not terminated by a stop codon [24].
• Nucleotide substitutions with a potential for phenotypic effects were found in the 12S and 16S rRNA and in the ND1 and COIII genes [25].

Analytical, diagnostic and therapeutic context of MT-CO3

• Northern Blot and quantitative real-time reverse transcription-PCR analysis further demonstrated that the primary ATP6--COX3 transcript is cleaved to the ATP6 and COX3 mRNAs 2-3-fold less efficiently [26].
• Sequence analysis of muscle mtDNA resulted in the identification of a virtually homoplasmic frameshift mutation in the COIII gene, due to the insertion of an extra C at nucleotide position 9537 of mtDNA [27].
• A PCR analysis of 21 cox3 clones, designed to measure the length of 5' and 3' ends separately, indicated that the greatest variability in length was found at the 3' end [12].
• In this study, the invariant carboxylic acids E98 (the DCCD-binding glutamic acid) and D259 of COIII were changed by site-directed mutagenesis to study their role in proton pumping [7].
• Northern hybridizations with potato and cauliflower (Brassica oleraceae) mtRNA and RT-PCR analyses using potato mtRNA indicated that cox3 and sdh4 are co-transcribed in both species, generating a complex transcription pattern, where several transcripts from 1.1 kb to 4.4 kb are found [28].

References