Inducible Impairment of Polymerase Gamma Activity in Cardiomyocytes Promotes Severe Cardiomyopathy with Cardiac Hepatopathy
Mitochondrial dysfunction is a hallmark feature of heart failure (HF) and cardiomyopathy, with substantial human and preclinical evidence suggesting that congenital mitochondrial defects can directly drive these conditions. Despite these strong links, not all individuals with mitochondrial disease develop cardiomyopathy, and therefore the precise mitochondrial defects that initiate cardiac pathology in this setting remain incompletely understood. Here, we describe a novel mouse model that induces progressive deterioration in mtDNA integrity specifically in cardiomyocytes. This model was generated through a post developmental, cardiomyocyte specific deletion of the exonuclease domain of Polymerase Gamma (PolG), impairing its ability to repair mtDNA. Strikingly, from just 16 weeks post-induction these mice displayed progressive worsening of cardiac output, ejection fraction, global strain and blood pressure culminating in premature death at 28-30 weeks post-mutation. Morphologically, these mice displayed cardinal features of hypertrophic cardiomyopathy with enlarged hearts, ventricles and cardiac fibrosis - but little evidence of congestive HF. We also demonstrate using various transcriptional and proteomic readouts, that signalling pathways characteristic of cardiomyopathy were activated. Interestingly, prior to substantial declines in cardiac function, we detect robust activation of the integrated stress response (ISR) in PolGMut mice, and major rewiring of mitochondrial folate metabolism pathways, suggesting that these pathways underpin the developing pathology. Lastly, we also observed a striking hepatopathy phenotype in mutant mice reminiscent of that observed in patients with HF, a condition not robustly recapitulated previously in other mouse models. Thus, our data establish a direct link between mtDNA instability leading to chronic activation of the ISR and rewiring of folate metabolism in cardiomyocytes, subsequently driving a severe cardiac phenotype associated with hepatopathy.