Mitochondrial dynamics and repair differences in two mouse models of Friedreich's ataxia

Friedreich's ataxia (FA) is an inherited disorder caused by reduced expression of the mitochondrial protein frataxin (FXN). Although defined as a neurodegenerative disease, cardiomyopathy is the leading cause of mortality. Cardiac manifestations of FA span from concentric hypertrophic cardiomyopathy with preserved systolic function and impaired diastolic relaxation, resembling heart failure with preserved ejection fraction (HFpEF), to systolic heart failure with reduced ejection fraction (HFrEF). The molecular mechanisms driving progression towards these cardiac phenotypes remain poorly understood. We examined mitochondrial content, dynamics and mitophagy in two FA mouse models: cardiac/skeletal muscle-specific MCK-Cre FXN knockout (FXN-cKO) mice, which develop HFrEF, and inducible FXN knockdown (FXNKD) mice, which develop HFpEF-like cardiomyopathy. FXN-cKO hearts exhibited increased mitochondrial transcription factor A expression, an elevated mitochondrial-to-nuclear DNA ratio and greater mitochondrial density by electron microscopy, consistent with enhanced mitochondrial biogenesis. In contrast, FXNKD hearts showed no changes in mitochondrial content or biogenesis markers. Mitochondrial dynamics were markedly altered in FXN-cKO hearts, with reduced mitofusin-2 and increased FIS1 expression, accompanied by smaller, fragmented mitochondria. FXNKD hearts exhibited preserved fission, modestly increased fusion and mild mitochondrial enlargement. Markers of mitophagy were increased in FXN-cKO hearts, but a reduced LC3-II/I ratio suggested impaired autophagosome maturation and defective mitochondrial clearance. No changes in mitophagy were observed in FXNKD hearts. These findings demonstrate that FA-associated HFrEF is characterized by increased mitochondrial biogenesis coupled with impaired mitochondrial quality control and fragmentation, whereas FA-associated HFpEF-like phenotype shows preserved mitochondrial architecture and turnover. Mitochondrial remodelling programmes may underlie divergent cardiac phenotypes in FA and represent therapeutic targets for disease modification. KEY POINTS: Friedreich's ataxia (FA) cardiomyopathy develops as heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF)-like disease, but mechanisms leading to different cardiac phenotypes are unclear. We compared mitochondrial remodelling in FA mouse models with divergent cardiac phenotypes. Frataxin knockout (FXN-cKO) mice with HFrEF phenotype showed increased mitochondrial biogenesis, fragmentation and impaired mitochondrial quality control. FXN knockdown (FXNKD) mice with HFpEF-like phenotype showed largely preserved mitochondrial structure and turnover. Distinct mitochondrial adaptations may drive phenotype-specific cardiac outcomes in FA.