Defective palmitoylation of transferrin receptor triggers iron overload in Friedreich's ataxia fibroblasts

Floriane Petit, Anthony Drecourt, Michaël Dussiot, Coralie Zangarelli, Olivier Hermine, Arnold Munnich, Agnes Rotig; Blood blood.2020006987. doi:10.1182/blood.2020006987 

 Here we report on abnormal cellular iron homeostasis in FRDA fibroblasts inducing a massive iron overload in the cytosol and mitochondria. We observe membrane transferrin receptor 1 (TfR1) accumulation, increased TfR1 endocytosis, and delayed transferrin recycling, ascribing this to impaired TfR1 palmitoylation. Frataxin deficiency is shown to reduce coenzyme A (CoA) availability for TfR1 palmitoylation. Finally, we demonstrate that artesunate, CoA, and dichloroacetate improve TfR1 palmitoylation and decrease iron overload, paving the road for evidence-based therapeutic strategies at the actionable level of TfR1 palmitoylation in FRDA.