The Dynamin-Related Protein 1 is Decreased and the Mitochondrial Network is Altered in Friedreich's Ataxia Cardiomyopathy

The mitochondrial anatomy in Friedreich ataxia hypertrophic cardiomyopathy is poorly understood. The authors 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. This study found a significantly higher mitochondrial footprint, decreased mitochondrial fission 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. In Friedreich ataxia human induced pluripotent stem cell cardiomyocytes, significantly depolarized mitochondrial membrane potential was observed, together with higher reactive oxygen species levels. These 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.

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