Polymorphic variation in cytochrome oxidase subunit genes
Open accessAbstract
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.
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Among 27 individuals in which exons of each COX gene were sequenced, no two individuals exhibited an identical composite genotype.
“Among 27 individuals in which the exons of each COX gene were sequenced, no two individuals exhibited an identical composite genotype.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [171]
Among fifty subjects, 20% had at least one non-synonymous polymorphism in the three mtDNA COX genes, and synonymous polymorphisms were even more common.
“We also sequenced the three mtDNA COX genes in fifty subjects. 20% had at least one non-synonymous polymorphism, and synonymous polymorphisms were even more common.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [171]
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References 50 · Cited by 33
- Authors
- Lu, J., Wang, K., Rodova, M., Esteves, R., Berry, D., E, L., Crafter, A., Barrett, M., Cardoso, S. M., Onyango, I., Parker, W. D., Fontes, J., Burns, J. M., & Swerdlow, R. H.
- Affiliations
- University of Kansas (US)
- University of Virginia Health System (US)
- Department of Neurology, University of Kansas School of Medicine, Kansas City, KS, USA
- Centro de Neurociências e Biologia Celular (PT)
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2010-07-08
- Volume
- 21
- Issue
- 1
- Pages
- 141-154
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC2910218
- OpenAlex
- W1508030134
- Cited by
- 33
- References
- 50
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2022: 2 · 2019: 3 · 2018: 1 · 2017: 2 · 2015: 3 · 2014: 2 · 2013: 4 · 2012: 2
- FWCI
- 1.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Commonwealth of Virginia
- University of Virginia
- National Institutes of Health
- National Institute on Aging (AG022407, R01AG022407, R01AG033673)
- National Center for Research Resources (P20RR016443)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- cytochrome c oxidase
- MeSH terms
- Cell Line, Transformed, Electron Transport Complex IV, DNA Mutational Analysis, DNA, Mitochondrial, Flow Cytometry, Humans, Molecular Sequence Data, Polymorphism, Genetic, Transfection, Protein Subunits, RNA, Small Interfering
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