The dynamin-related protein 1 is decreased and the mitochondrial network is altered in Friedreich's ataxia cardiomyopathy.

Friedreich ataxia is an autosomal recessive congenital neurodegenerative disease caused by a deficiency in the frataxin protein and is often diagnosed in young adulthood. An expansion of guanine-adenine-adenine repeats in the first intron of the FXN gene leads to decreased frataxin expression. Frataxin plays an essential role in mitochondrial metabolism. Most Friedreich ataxia patients are diagnosed with left ventricular hypertrophic cardiomyopathy, and 60% of patients die with hypertrophic cardiomyopathy. However, the mitochondrial anatomy in Friedreich ataxia hypertrophic cardiomyopathy is still poorly understood. We investigated mitochondrial fission, fusion, and function using biochemical, microscopy, and computational stochastic analysis in human induced pluripotent stem cell derived cardiomyocytes from a patient with Friedreich ataxia hypertrophic cardiomyopathy and a healthy individual. We found a significantly higher mitochondrial footprint, decreased mitochondrial fission protein dynamin-related protein, and mitochondrial fission rate over fusion with more giant mitochondrial clusters in human induced pluripotent stem cell derived cardiomyocytes from a patient with Friedreich ataxia hypertrophic cardiomyopathy, compared to an unaffected individual. We also found significantly depolarized mitochondrial membrane potential and higher reactive oxygen species levels in Friedreich ataxia human induced pluripotent stem cell cardiomyocytes. Our results show that frataxin's depletion may dampen the mitochondrial fission machinery by reducing dynamin-related protein1. The loss of mitochondrial fission might lead to elevated reactive oxygen species and depolarized mitochondrial membrane potential, which may cause oxidative damage in Friedreich ataxia hypertrophic cardiomyopathy. Further investigations are needed to identify the mechanism of downregulating dynamin-related protein1 due to the frataxin deficiency in Friedreich ataxia hypertrophic cardiomyopathy.

Generation of a Friedreich's Ataxia patient-derived iPSC line USFi001-A.

Friedreich's Ataxia (FA) is an autosomal recessive disorder with an incidence of 1 in 50,000 in Caucasians. Most cases are caused by a biallelic GAA expansion in the first intron of the Frataxin (FXN) gene. FA is a neurodegenerative disease, but the leading cause of death is hypertrophic cardiomyopathy (HCM) that develops in 60% of the patients. We generated an induced pluripotent stem cell (iPSC) line from an FA patient with a homozygous GAA expansion in intron 1 of the FXN gene. The IPSCs display pluripotent cell morphology, expression of pluripotency markers, normal karyotype, and the capability to differentiate into all three germ layers.