Impaired dynamics and function of mitochondria caused by mtDNA toxicity leads to heart failure
Knut H Lauritzen1, Liv Kleppa1, Jan Magnus Aronsen2
1Department of Oral Biology, Brain and Muscle Energy Group, University of Oslo, Oslo, Norway; Department of Anatomy, Institute of Basic Medical Sciences, and Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway;
Abstract:
Cardiac mitochondrial dysfunction has been implicated in heart failure of diverse etiologies. Generalized mitochondrial disease also leads to cardiomyopathy with various clinical manifestations. Impaired mitochondrial homeostasis may over time, such as in the aging heart, lead to cardiac dysfunction. Mitochondrial DNA (mtDNA), close to the electron transport chain and unprotected by histones, may be a primary pathogenetic site, but this is not known. Here, we test the hypothesis that cumulative damage of cardiomyocyte mtDNA leads to cardiomyopathy and heart failure. Transgenic mice with Tet-on inducible, cardiomyocyte-specific expression of a mutant uracil-DNA glycosylase 1 (mutUNG1) were generated. The mutUNG1 is known to remove thymine in addition to uracil from the mitochondrial genome, generating apyrimidinic sites, which obstruct mtDNA function. Following induction of mutUNG1 in cardiac myocytes by administering doxycycline, the mice developed hypertrophic cardiomyopathy, leading to congestive heart failure and premature death after ∼2 mo. The heart showed reduced mtDNA replication, severely diminished mtDNA transcription, and suppressed mitochondrial respiration with increased Pgc-1α, mitochondrial mass, and antioxidative defense enzymes, and finally failing mitochondrial fission/fusion dynamics and deteriorating myocardial contractility as the mechanism of heart failure. The approach provides a model with induced cardiac-restricted mtDNA damage for investigation of mtDNA-based heart disease.
Insights
Cumulative damage to mitochondrial DNA (mtDNA) in heart cells causes cardiomyopathy and heart failure. This study introduces a new mouse model to investigate mtDNA-related heart disease.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Genetics
Background:
- Cardiac mitochondrial dysfunction is linked to various heart failure causes.
- Aging hearts can develop cardiac dysfunction due to impaired mitochondrial homeostasis.
- Mitochondrial DNA (mtDNA) damage is a potential, yet unconfirmed, cause of heart disease.
Purpose of the Study:
- To test the hypothesis that cumulative cardiomyocyte mtDNA damage leads to cardiomyopathy and heart failure.
- To establish a novel animal model for studying mtDNA-based heart disease.
Main Methods:
- Generated transgenic mice with inducible, cardiomyocyte-specific expression of mutant uracil-DNA glycosylase 1 (mutUNG1).
- Administered doxycycline to induce mutUNG1, causing thymine and uracil removal from mtDNA, creating apyrimidinic sites.
- Analyzed cardiac function, mtDNA replication and transcription, mitochondrial respiration, and dynamics.
Main Results:
- Induced mutUNG1 expression led to hypertrophic cardiomyopathy, congestive heart failure, and premature death in mice.
- Observed reduced mtDNA replication and transcription, suppressed mitochondrial respiration, and increased Pgc-1α and mitochondrial mass.
- Detected impaired mitochondrial fission/fusion dynamics and deteriorating myocardial contractility.
Conclusions:
- Cumulative cardiomyocyte mtDNA damage is a direct cause of cardiomyopathy and heart failure.
- The developed mouse model effectively mimics mtDNA-based heart disease, enabling further research.
- Findings highlight the critical role of mtDNA integrity in maintaining cardiac function.
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