Mitochondrial polymerase gamma dysfunction and aging cause cardiac nuclear DNA methylation changes.

Area of Science:

• Molecular Biology
• Cardiovascular Science
• Epigenetics

Background:

• Cardiomyopathy (CM) involves myocardial weakening, contractile dysfunction, and congestive heart failure (CHF), potentially linked to reduced mitochondrial energy production and oxidative stress.
• Aging exacerbates mitochondrial dysfunction, impacting cardiac health.
• Previous studies indicated DNA methylation changes and mitochondrial DNA depletion in human CM hearts.

Purpose of the Study:

• To investigate the relationship between mitochondrial dysfunction and cardiac epigenetic DNA methylation changes in young and old mice.
• To determine how cardiac-specific mitochondrial polymerase-gamma (Y955C) mutation and aging affect gene expression and DNA methylation.

Main Methods:

• Utilized genetically engineered C57Bl/6 mice with a cardiac-specific mutant mitochondrial polymerase-gamma (Y955C).
• Analyzed gene expression and DNA methylation patterns in young (Y955C) and old mice.
• Compared methylation patterns and differentially expressed genes between Y955C and aged hearts.

Main Results:

• Y955C expression resulted in 95 differentially expressed genes, while aging affected 4,452 genes.
• Y955C hearts showed 4,506 differentially methylated regions (68.5% hypomethylated), and aged hearts had 73,286 (80.2% hypomethylated).
• A significant overlap was found between Y955C-dependent differentially expressed genes and DNA methylation changes (31.6%), and similarly for age-dependent genes (7.7%). Both groups showed enrichment of CACGTG-associated E-box motifs.

Conclusions:

• Cardiac mitochondrial polymerase dysfunction directly alters nuclear DNA methylation.
• Aging induces substantial changes in cardiac DNA methylation, with a portion associated with mitochondrial polymerase dysfunction.
• These findings highlight the interplay between mitochondrial health, aging, and epigenetic modifications in the heart.