Mitochondrial DNA Dysfunction in Cardiovascular Diseases: A Novel Therapeutic Target.

Area of Science:

• Cardiology
• Mitochondrial Biology
• Immunology

Background:

• Cardiovascular diseases (CVDs) are linked to a cycle of mitochondrial deoxyribonucleic acid (mtDNA) dysfunction.
• Cardiac energy production relies heavily on oxidative phosphorylation (OXPHOS), making it vulnerable to mtDNA damage.
• mtDNA insults impair ATP production, increase reactive oxygen species (ROS), and damage the mitochondrial genome.

Purpose of the Study:

• To review the role of mtDNA dysfunction in a unifying pathogenic cycle in cardiovascular diseases.
• To explore implications of this cycle for various mtDNA-driven cardiac disorders.
• To evaluate therapeutic strategies targeting mtDNA integrity and innate immune activation.

Main Methods:

• Literature review synthesizing pathophysiological roles of mtDNA in cardiovascular disease.
• Evaluation of preclinical and clinical strategies for interrupting the mtDNA damage cycle.
• Discussion of current gaps in translating mitochondrial genome medicine for CVDs.

Main Results:

• mtDNA dysfunction impairs cardiac bioenergetics and triggers sterile inflammation.
• Escaped mtDNA fragments activate cytosolic innate immune pathways (e.g., cGAS-STING, TLR9, NLRP3).
• This activation leads to cytokine storms, pyroptosis, and tissue injury, forming a self-amplifying cycle.

Conclusions:

• The proposed mtDNA dysfunction cycle is a unifying mechanism in cardiovascular diseases.
• Strategies to repair mtDNA, maintain copy number, reverse methylation, and block immune activation are promising.
• Bridging research gaps is crucial for developing precision mitochondrial genome medicine for CVDs.