Retention of a Duplicate Gene Through Changes in Subcellular Targeting: An Electron Transport Protein Homologue Localizes to the Golgi

Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Journal of Molecular Evolution (Impact Factor: 1.68). 09/2003; 57(2):222-8. DOI: 10.1007/s00239-003-2468-8
Source: PubMed


Cytochrome c oxidase (COX), the terminal enzyme complex of the electron transport chain, contains 13 subunits, 3 encoded by mitochondrial DNA and 10 by nuclear. Several of the nuclear subunits, including subunit VIIa, are known to have two tissue- and development-specific isoforms in mammals. A recently identified third member of the gene family, COX7AR, encodes a protein previously thought to function in mitochondria. However, observation of fluorescent pCOX7AR C-terminal fusion proteins in HeLa cells showed that pCOX7AR is localized to the Golgi apparatus. Sequence analyses indicate that the duplication of COX7AR occurred prior to the origin of the Euteleostomi (bony vertebrates) and that pCOX7AR is more highly conserved than the two other isoforms. These results indicate that, after gene duplication and modification of the mitochondrial targeting signal, pCOX7AR was evolutionarily altered to a new and apparently important function in the Golgi. These results also suggest that predictions of function from homology can be misleading and show that specialization and modification of subcellular localization are similar to cis-element subfunctionalization. In cis-element subfunctionalization, complementary null mutations occur to the cis-elements of the descendents of a gene duplication, causing both descendent genes to be obligate. In the process described in this paper, which could be termed subcellular subfunctionalization, complementary null mutations can occur to the subcellular localization signals of the descendants of a gene duplication, causing both descendent genes to be similarly obligate. Noncomplementary null mutations could also uncover an alternate localization, which is the more likely case for pCOX7AR.

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    • "The designation COX includes the COX7AL isoform in liver and the COX7AH isoform in heart and skeletal muscle (Seelan, et al., 1996). COX 7 AR gene is expressed in all tissue types, and Schmidt et al. (2003) showed that in HeLa cells the third isoform is localized to the Golgi apparatus (COX7AR). Recent study indicates that the expression of the mtDNA coded genes is not significantly altered in aged Fisher À344 rat ventricles (Preston et al., 2008). "
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    ABSTRACT: Aging decreases oxidative phosphorylation through cytochrome oxidase (COX) in cardiac interfibrillar mitochondria (IFM) in 24-month old (aged) rats compared to 6-month old adult Fischer 344 rats, whereas subsarcolemmal mitochondria (SSM) located beneath the plasma membrane remain unaffected. Immunoelectron microscopy (IEM) reveals in aged rats a 25% reduction in cardiac COX subunit VIIa in cardiac IFM, but not in SSM. In contrast, the content of subunit IV remains unchanged in both SSM and IFM, irrespective of age. These subunits are localized mainly on cristae membranes. In contrast, semi-quantitative immunoblotting, which detects denatured protein, indicates that the content of COX VIIa is similar in IFM and SSM from both aged and adult hearts. IEM provides a sensitive method for precise localizing and quantifying specific mitochondrial proteins. The lack of immunoreaction of COX VIIa subunit by IEM in aged IFM is not explained by a reduction in protein, but rather by a masking phenomenon or by an in situ change in protein structure affecting COX activity.
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    • "Sub-functionalization and neofunctionalization allow spatio-temporal specialization and expansion of functionality, respectively, but it is usually difficult to draw a line between the two fates (He & Zhang, 2005). There are several studies of spatial sub/neo-functionalization revealing the function of paralogues as either tissue-specific (for example, in zebrafish, pax6a and pax6b paralogues are expressed in different tissues and both of them fulfil the functional role of mammalian pax6; Kleinjan et al, 2008) or even within a single cell compartment (for example, the paralogues of the mammalian COX7A family are expressed in either the mitochondrion or the Golgi; Schmidt et al, 2003). Although a few studies observe distinct expression profiles of duplicates during the developmental time scale (Bassham et al, 2008; Kleinjan et al, 2008), the role of duplicated genes in the temporal organization of the cell remains unclear (Gu et al, 2002; Wagner, 2002). "
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    • "lineage. The subcellular localization (targeting) innovation has been described in the case of the cox gene family (Schmidt et al., 2003). After duplication event, one of the gene copies still encodes for a protein located in the mitochondria whereas the paralogous gene (the other copy) codes for a product located in the Golgi apparatus. "
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