Top Things to Know: Mitochondrial Genetics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association
Published: December 02, 2025
Prepared by Jessica L. Fetterman, PhD, FAHA
- The mitochondrial genome is a double-stranded, circular genome that is exclusively maternally inherited.
- The mitochondrial genome encodes essential parts of four oxidative phosphorylation complexes and the RNAs for their expression, which generate most ATP in the heart. The rest of these complexes and other mitochondrial proteins are encoded by the nuclear genome; therefore, both genomes must coordinate for proper mitochondrial function.
- Mitochondrial genetics is complex, as each mitochondrion contains multiple mitochondrial genomes, and different copies of the mitochondrial genome may carry different variants, termed heteroplasmy. Heteroplasmic variants are known to increase with age and may contribute to cardiovascular diseases (CVD).
- Variants in mitochondrial genes of either the nuclear or mitochondrial genomes are known to cause mitochondrial diseases, rare metabolic disorders that predominantly affect highly energetic tissues. No therapies are approved for the treatment of mitochondrial diseases, in part due to our limited understanding of the factors contributing to disease heterogeneity.
- Population-level studies have identified mitochondrial DNA variants associated with CV risk factors and disease, yet evaluation of mitochondrial DNA genetic variation is often limited to only a handful of variants and in small sample sizes.
- Next-generation sequencing allows for the identification of mitochondrial DNA variants at an unprecedented resolution, facilitating population-level and mechanistic studies of mitochondrial DNA variation and improved diagnosis of mitochondrial disease.
- Studies in animal models have linked several mitochondrial DNA variants to cardiac remodeling and dysfunction and suggest a role for mitochondrial-nuclear genetic interactions in disease penetrance.
- Recent advances have enabled the creation of induced pluripotent stem cells from patients with pathogenic mitochondrial DNA variants for disease modeling. However, these cells have not yet been fully used to understand how specific variants affect cardiomyocyte phenotype.
- Advancements in bioinformatics, mitochondrial DNA editing, and single-cell techniques are enhancing our understanding of mitochondrial genetics in CV biology and disease.
- This statement summarizes key practices in identifying mitochondrial DNA variants, reviews current knowledge of their role in CVD disease, and identifies existing gaps in understanding.
Citation
Fetterman JL, Chinnery PF, McClellan R, Wallace DC, Suomalainen A, Ojala T, Lewis SC, Ballinger SW; on behalf of the American Heart Association Council on Genomic and Precision Medicine; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Cardiovascular and Stroke Nursing; and Council on Peripheral Vascular Disease. Mitochondrial genetics in cardiovascular health and disease: a scientific statement from the American Heart Association. Circulation. Published online December 2, 2025. doi: 10.1161/CIR.0000000000001393