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Published on: August 8, 2022
Mice deleted for heart-type cytochrome c oxidase subunit 7a1 develop dilated cardiomyopathy
Maik Hüttemann1, Scott Klewer, Icksoo Lee
1Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Abstract:
Subunit 7a of mouse cytochrome c oxidase (Cox) displays a contractile muscle-specific isoform, Cox7a1, that is the major cardiac form. To gain insight into the role of this isoform, we have produced a new knockout mouse line that lacks Cox7a1. We show that homozygous and heterozygous Cox7a1 knockout mice, although viable, have reduced Cox activity and develop a dilated cardiomyopathy at 6 weeks of age. Surprisingly, the cardiomyopathy improves and stabilizes by 6 months of age. Cox7a1 knockout mice incorporate more of the "liver-type" isoform Cox7a2 into the cardiac Cox holoenzyme and, also surprisingly, have higher tissue ATP levels.
Insights
Mice lacking the cardiac cytochrome c oxidase 7a1 (Cox7a1) subunit develop dilated cardiomyopathy, but it improves with age. These knockout mice show altered Cox enzyme composition and increased tissue ATP levels.
Area of Science:
- Mitochondrial respiration
- Cardiac physiology
- Gene knockout models
Background:
- Cytochrome c oxidase (Cox) is crucial for cellular respiration.
- Cox subunit 7a1 (Cox7a1) is a muscle-specific isoform and the primary cardiac form.
- Understanding Cox7a1's role is vital for cardiac health.
Purpose of the Study:
- To investigate the function of Cox7a1 in the heart.
- To characterize the cardiac phenotype of Cox7a1-deficient mice.
Main Methods:
- Generation of a Cox7a1 knockout mouse model.
- Assessment of cardiac function and Cox activity.
- Analysis of Cox holoenzyme composition and tissue ATP levels.
Main Results:
- Cox7a1 knockout mice exhibit reduced cardiac Cox activity.
- A dilated cardiomyopathy develops in young knockout mice, which surprisingly improves by 6 months.
- Knockout mice show increased incorporation of Cox7a2 and elevated tissue ATP levels.
Conclusions:
- Cox7a1 is essential for normal cardiac Cox activity and function.
- Cardiac function in Cox7a1 deficiency can partially recover over time.
- Alternative Cox isoforms and metabolic adaptations play a role in compensating for Cox7a1 loss.
