Key result
Cardiomyocyte mtDNA mutations autonomously drive progressive contractile dysfunction and local inflammation independent of systemic aging.
Why the study?
It remained unclear whether premature aging phenotypes from somatic mtDNA mutations result from systemic dysfunction or cell-intrinsic effects.
Cardiomyocyte-intrinsic mtDNA mutations are sufficient to drive progressive heart failure and local immune responses, linking mitochondrial dysfunction to cardiac aging.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“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.”
“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.”
Cardiomyocyte mtDNA mutations may drive age-related HF in mice; leaves open human relevance and need for prospective validation.
Mitochondrial DNA (mtDNA) mutations accumulate with age, but their mechanistic contribution to aging remains unclear. The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLG D257A ) and accumulates mtDNA mutations across all tissues leading to premature aging. However, this model cannot resolve whether the aging phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations. To overcome this limitation, we generated Polg iMut mice allowing spatial and temporal control of POLG D257A expression. We demonstrate here that mtDNA mutations induced in cardiomyocytes cause progressive contractile dysfunction and respiratory chain deficiency in the heart without accompanying systemic pathology. Proteomic analyses link cardiac mosaic respiratory chain dysfunction to a progressive immune response, characterized by up-regulation of antigen-processing proteins and immune cell infiltration. In contrast, longevity-associated pathways are suppressed and uncoupled from mitochondrial and immune alterations, indicating distinct regulatory mechanisms. These findings demonstrate that mtDNA mutations can drive cardiac dysfunction and reveal a mechanistic link between mitochondrial dysfunction, immune responses, and aging.
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Bubb et al. (2026) studied Heart failure and aging. Cardiomyocyte-specific expression of proofreading-deficient mtDNA polymerase (POLG D257A) vs. Littermate control mice was evaluated on Cardiac contractile dysfunction (fractional shortening) and respiratory chain deficiency. Cardiomyocyte-intrinsic accumulation of mtDNA mutations autonomously drove progressive cardiac contractile dysfunction, metabolic reprogramming, and local immune responses independent of systemic aging pathology.
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