The cardiac calcium handling machinery is remodeled in Friedreich ataxia

Friedreich ataxia (FA) is a progressive neurodegenerative disorder caused by an expansion of the GAA triplet repeat in the frataxin (FXN) gene, leading to reduced FXN expression. FA commonly affects the heart, causing hypertrophy, heart failure, and fibrosis. The mechanisms of FA-associated cardiac dysfunction may involve disrupted calcium (Ca²⁺) handling and mitochondrial impairment.

This study aimed to investigate whether abnormalities in Ca²⁺ handling machinery contributes to cardiac dysfunction in FA.

Human left ventricular tissue from patients with FA and unaffected donors, and an FXN knock-out (FXN-KO) mouse model, were analyzed. In mice, cardiac function was assessed by echocardiography and electrocardiography. The expression of Ca²⁺-handling proteins was evaluated with Western blotting, quantitative real-time polymerase chain reaction, and immunofluorescence. Single-cell contractility and Ca²⁺ transients were measured in isolated ventricular myocytes. Mitochondrial function was assessed via confocal imaging to quantify mitochondrial membrane potential (Δψ_m) and reactive oxygen species.

FXN-KO mice exhibited significant reductions in ejection fraction, stroke volume, fractional shortening, and cardiac output, with increased left ventricular mass and elevated end-diastolic and end-systolic volumes. Strain analysis revealed increased global and peak longitudinal strain. On electrocardiogram, the RR, PR, QRS, and QTc intervals were prolonged. Both human FA and FXN-KO hearts showed downregulation of sarco or endoplasmic reticulum Ca²⁺-ATPase 2a and ryanodine receptor 2, with reduced phospholamban phosphorylation. FXN-KO mice also showed upregulation of mitochondrial Ca²⁺-handling proteins, including mitochondrial Ca²⁺ uniporter and voltage-dependent anion channel, depolarized Δψ_m, and elevated reactive oxygen species.

Cardiac dysfunction in FA is associated with impaired Ca²⁺ handling, mitochondrial dysregulation, and systolic impairment, identifying potential molecular targets for therapy.