Mitochondrial DNA mutations: more than a marker of aging
Researchers at Karolinska Institutet have shown that mutations in mitochondrial DNA (mtDNA), which accumulate in many tissues as we age, can actively contribute to impaired heart function. Until now, it has been difficult to determine whether these mutations are a cause of age-related heart dysfunction or simply a consequence of aging. The findings, published in Science Advances, provide direct evidence that acquired mtDNA mutations can themselves drive tissue dysfunction and cause heart failure
Mitochondria harvest the energy our cells need and contain their own genetic material, known as mtDNA. Random mutations arise in mtDNA throughout life and build up unevenly across cells and tissues. Because this happens alongside many other changes during aging, it has been difficult to separate the specific impact of mtDNA mutations from the aging process itself.
To overcome this, the researchers developed a new mouse model that allows mtDNA mutations to accumulate progressively in selected cell types. In this study, the model was used to induce mtDNA mutations in cardiac muscle cells, allowing the researchers to follow how a rising mutation burden affects heart function.
“What we could show with this model is that the number of mtDNA mutations matters. As the mutations accumulated, mitochondrial function declined, and the heart became less able to contract. This allowed us to directly link an increasing burden of acquired mtDNA mutations to a progressive loss of heart function,” says Kristina Bubb, Postdoctoral Researcher at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and one of the first authors of the study.
“Importantly, the effects were not limited to an energy deficit in heart muscle cells. Mitochondrial dysfunction was accompanied by immune cell recruitment and increasing fibrosis, showing that mitochondrial damage is sensed by the immune system and triggers a response that will further worsen heart function,” says Nils-Göran Larsson, professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and corresponding author of the study.
Together, the findings show that the effects of accumulating mtDNA mutations extend beyond mitochondrial dysfunction itself, setting off inflammatory and fibrotic responses that may further contribute to declining tissue function. The new model can now be used to uncover how these responses arise and how they contribute to aging and age-related disease in different tissues.
Publication
Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
Bubb K, Rigoni G, Papadea P, Pironti G, Misic J, Jiang S, Alsina D, Rubalcava-Gracia D, Andersson DC, Filograna R, Koolmeister C, Giavalisco P, Wredenberg A, Mann M, Rosenberger FA, Larsson NG
Sci Adv 2026 Sep;12(36):eaec8606