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Updated: Jun 1, 2025
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
MnSOD non-acetylation mimic knock-in mice exhibit dilated cardiomyopathy
Joseph R Schell1, Sung-Jen Wei1, Jun Zhang2
1Department of Radiation Oncology, Mays Cancer Center at UT Health San Antonio MD Anderson, Joe R. and Teresa Lozano Long School of Medicine, TX, USA; Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, TX, USA.
Abstract:
Manganese superoxide dismutase (MnSOD/SOD2) is an essential mitochondrial enzyme that detoxifies superoxide radicals generated during oxidative respiration. MnSOD/SOD2 lysine 68 acetylation (K68-Ac) is an important post-translational modification (PTM) that regulates enzymatic activity, responding to nutrient status or oxidative stress, and elevated levels have been associated with human illness. To determine the in vivo role of MnSOD-K68 in the heart, we used a whole-body non-acetylation mimic mutant (MnSODK68R) knock-in mouse. These mice exhibited several cardiovascular phenotypes, including lower blood pressure, decreased ejection fraction, and importantly, dilated cardiomyopathy, as evidenced by echocardiography at four months of age. In addition, both mouse embryo fibroblasts (MEFs) and cardiovascular tissue from MnSODK68R/K68R mice exhibited an increase in cellular senescence. Finally, MnSODK68R/K68R mouse hearts also showed an increase in lipid peroxidation. We conclude that constitutively active MnSOD detoxification activity, lacking the normal switch between non-acetylated and acetylated forms, dysregulates mitochondrial physiology during development, leading to dilated cardiomyopathy.
Insights
Manganese superoxide dismutase (MnSOD/SOD2) acetylation regulates heart function. A non-acetylation mimic mutant (MnSODK68R) caused dilated cardiomyopathy, increased senescence, and lipid peroxidation in mice.
Area of Science:
- Mitochondrial biology
- Cardiovascular research
- Biochemistry
Background:
- Manganese superoxide dismutase (MnSOD/SOD2) is a key mitochondrial enzyme for detoxifying superoxide radicals.
- Lysine 68 acetylation (K68-Ac) of MnSOD/SOD2 is a post-translational modification regulating its activity in response to cellular conditions.
- Dysregulated MnSOD/SOD2 activity and acetylation are linked to human diseases.
Purpose of the Study:
- To investigate the in vivo role of MnSOD-K68 acetylation in cardiac function.
- To elucidate the impact of a non-acetylation mimic mutant on cardiovascular health and mitochondrial physiology.
Main Methods:
- Generation of a whole-body non-acetylation mimic mutant mouse model (MnSODK68R).
- Cardiovascular phenotyping using echocardiography.
- Assessment of cellular senescence in mouse embryo fibroblasts (MEFs) and cardiac tissue.
- Analysis of lipid peroxidation in MnSODK68R/K68R mouse hearts.
Main Results:
- MnSODK68R/K68R mice displayed cardiovascular abnormalities, including lower blood pressure and decreased ejection fraction.
- Dilated cardiomyopathy was a prominent phenotype observed in these mice.
- Increased cellular senescence and lipid peroxidation were detected in MnSODK68R/K68R mice.
- Constitutive MnSOD activity dysregulated mitochondrial physiology during development.
Conclusions:
- The inability of MnSOD/SOD2 to undergo normal acetylation/deacetylation cycles impairs mitochondrial function.
- Disruption of MnSOD/SOD2 acetylation regulation leads to dilated cardiomyopathy and associated pathologies.
- This study highlights the critical role of MnSOD/SOD2 post-translational modifications in maintaining cardiovascular health.
