Tiny genome with big impact: mitochondrial DNA in cardiovascular health

Cardiovascular diseases remain the leading cause of mortality worldwide. Mitochondrion, a key cellular organelle, harbors its own mitochondrial DNA (mtDNA) fundamental to cellular energy production through oxidative phosphorylation (OXPHOS). Beyond its canonical bioenergetic function, mtDNA integrity, copy number, and genetic variation play critical roles in maintaining cardiovascular function. This review provides a comprehensive overview of the multifaceted contributions of mtDNA to cardiovascular health and disease. We summarize the structural features and core biological functions of mtDNA, as well as the regulatory mechanisms governing its replication, biogenesis, and turnover. Particular emphasis is focused on mtDNA abnormalities, including point mutations, large-scale deletions, copy number alterations, and epigenetic modifications, and how these disturbances drive key pathogenic processes such as oxidative stress, chronic inflammation, apoptosis, and cellular senescence within the cardiovascular system. Furthermore, we highlight accumulating evidence linking mtDNA dysregulation to major cardiovascular disorders, including heart failure, atherosclerosis, and hypertension. Finally, we discuss the emerging diagnostic potential of circulating cell-free mtDNA and related mtDNA-derived metrics as non-invasive biomarkers, and outline therapeutic strategies aimed at preserving mtDNA integrity, modulating mtDNA content, or applying gene-based interventions to mitigate cardiovascular pathology.