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Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy
Dekui Zhang1, Justin L Mott, Patricia Farrar
1Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, 1402 South Grand Boulevard, St. Louis, MO 63104, USA.
Objective:
To determine whether low frequency mitochondrial DNA (mtDNA) mutations are pathogenic.
Methods:
We studied mice that express a proofreading-deficient mitochondrial DNA polymerase in the heart and develop cardiac mtDNA mutations.
Results:
At 4 weeks of age, when point mutation levels had risen to on average two per mitochondrial genome, these mice developed severe dilated cardiomyopathy. Interstitial fibrosis first became apparent at 4 weeks of age and progressed with age. Sporadic myocytic death occurred in all regions of the heart, apparently due to apoptosis as assessed by histological analysis and TUNEL staining. The frequency of TUNEL-positive cells peaked at 4-5 weeks of age and then gradually declined. While mitochondrial respiratory function, ultrastructure, and number remained normal, cytochrome c was released from mitochondria, a known apoptotic signal.
Conclusion:
mtDNA mutations therefore are pathogenic, and seem to trigger apoptosis through the mitochondrial pathway.
Insights
Mitochondrial DNA (mtDNA) mutations are pathogenic, causing severe heart disease and cell death in mice. These mutations trigger apoptosis, a programmed cell death pathway, through the mitochondria.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Mitochondrial DNA (mtDNA) mutations are implicated in various diseases.
- The pathogenicity of low-frequency mtDNA mutations remains unclear.
Purpose of the Study:
- To investigate whether low-frequency mitochondrial DNA (mtDNA) mutations are pathogenic.
- To elucidate the mechanism by which mtDNA mutations affect cardiac health.
Main Methods:
- Studied mice engineered to express a proofreading-deficient mitochondrial DNA polymerase in the heart.
- Induced cardiac mtDNA mutations and analyzed their effects on cardiac function and histology.
Main Results:
- Mice developed severe dilated cardiomyopathy and interstitial fibrosis by 4 weeks of age.
- Apoptosis (programmed cell death) was observed in cardiac myocytes, indicated by TUNEL staining.
- Cytochrome c release from mitochondria, a pro-apoptotic signal, occurred despite normal mitochondrial respiratory function.
Conclusions:
- Mitochondrial DNA (mtDNA) mutations are confirmed as pathogenic.
- These mutations appear to trigger apoptosis via the intrinsic mitochondrial pathway.