Cytochrome c Oxidase Subunit VIIa Heart Isoform (COX7AH) Knockout Mice as an Animal Model for Studying Dilated Cardiomyopathy
Lee, Michael Y.
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Complex IV of the electron transport chain, cytochrome c oxidase (COX), facilitates the reduction of oxygen into water and pumps protons into the intermembrane space of mitochondria. In mammals COX contains 13 subunits, most of which are encoded by nuclear DNA and most have uncharacterized functions. Some subunits express tissue specific isoforms, isoforms are different versions of the same subunit coded by separate genes. Subunit VIIa is expressed as “heart” and “liver” type isoforms, the former of which is predominantly expressed in cardiac and skeletal muscles. The heart isoform gene (COX7AH) was knocked out in a mouse model to characterize its function. Transgenic mice demonstrated non-lethal physiological symptoms of dilated cardiomyopathy, a form of cardiac dysfunction with multiple molecular causes including cellular and mitochondrial dysfunction. To study the transcriptional effect of COX7AH knockout, mRNA transcripts of genes related to mitochondrial function were measured using quantitative real-time polymerase chain reaction (qPCR) across wild-type, heterozygous, and COX7AH knockout mice. The current study suggests that the liver isoform of subunit VIIa (COX7AL) compensated through upregulated expression in absence of COX7AH. Transcripts of ATP5a1, Tfam, Sod2, and Sdha demonstrated decreases in gene expression in the knockout mice. In addition, ATP levels from hearts were measured and showed no significant difference in knockout mice. Our study suggests possible causes for the benign dilated cardiomyopathy in COX7AH knockout mice including COX7AL compensation, metabolic shift, and unstressed conditions. Further biochemical, physiological, and genetic studies are needed to further elucidate functional significance of COX7AH.