Polymorphic Variation in Cytochrome Oxidase Subunit Genes

Abstract

Cytochrome oxidase (COX) activity varies between individuals and low activities associate with Alzheimer's disease. Whether genetic heterogeneity influences function of this multimeric enzyme is unknown. To explore this we sequenced three mitochondrial DNA (mtDNA) and ten nuclear COX subunit genes from at least 50 individuals. 20% had non-synonymous mtDNA COX gene polymorphisms, 12% had a COX4I1 non-synonymous G to A transition, and other genes rarely contained non-synonymous polymorphisms. Frequent untranslated region (UTR) polymorphisms were seen in COX6A1, COX6B1, COX6C, and COX7A1; heterogeneity in a COX7A1 5' UTR Sp1 site was extensive. Synonymous polymorphisms were common and less frequent in the more conserved COX1 than the less conserved COX3, suggesting at least in mtDNA synonymous polymorphisms experience selection pressure and are not functionally silent. Compound gene variations occurred within individuals. To test whether variations could have functional consequences, we studied the COX4I1 G to A transition and an AGCCCC deletion in the COX7A1 5' UTR Sp1 site. Cells expressing the COX4I1 polymorphism had reduced COX Vmax activity. In reporter construct-transduced cells where green fluorescent protein expression depended on the COX7A1 Sp1 site, AGCCCC deletion reduced fluorescence. Our findings indicate COX subunit gene heterogeneity is pervasive and may mediate COX functional variation.

Insights into Mitochondrial Dysfunction: Aging, Amyloid-β, and Tau–A Deleterious Trio

“…Indeed, defects in mtDNA associated with decreased cytochrome oxidase activity have been found in AD patients (9). Although a similarly impaired mitochondrial function and subsequent compensatory response have been observed in both nondemented aged and AD subjects, no clear causative mutations in the mtDNA have been correlated to AD; although some variations have functional consequences, including changes in enzymatic activity (40). Perhaps the main differences are that, in AD brains, defects are more profound due to Ab and tau accumulation, because of decreased compensatory response machinery (Fig.…”

Nonautosomal Genetic Variation in Carotenoid Coloration

“…However, estimates of heritability may 80 be biased if non-autosomal sources of heritable variation are present but not modeled, leading to erroneous conclusions about the evolvability of a trait. Based on the shared biochemical pathways of intracellular energy production and the oxidation of carotenoids, Johnson and Hill (2013) recently suggested that carotenoid metabolism takes place at the inner mitochondrial membrane, highlighting the potential for functional sequence variation in the mitochondrial 85 genome (Lu et al 2010) to impact directly on coloration, much as it impacts aerobic performance (Harrison and Turrion-Gomez 2006;Niemi and Majamaa 2005). Given that mitochondria are maternally inherited (Brown 2008; though paternal leakage of mitochondrial DNA has been reported in birds: Kvist et al 2003), this raises the possibility that variation in carotenoid-based coloration is associated with extranuclear genetic variation.…”

Mitochondrial DNA Oxidative Damage and Repair in Aging and Alzheimer's Disease

“…Moreira (130) and de la Monte (46) reported that AD brains present increased fragmentation of mtDNA, reduced mtDNA content and mass, reduced level of COX, and evidence of apoptotic cell loss. Despite no causative mtDNA mutations being linked to AD, some polymorphic variations can occur, having implications in enzymatic activities, such as COX (109). Some mtDNA mutations have been associated with increased incidence of AD (195,43).…”