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

Frataxin deficiency in Friedreich's ataxia (FRDA) affects ISC-containing proteins and causes iron to accumulate in the brain and heart of FRDA patients. This study reports on abnormal cellular iron homeostasis in FRDA fibroblasts inducing a massive iron overload in the cytosol and mitochondria. The authors 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, this study demonstrates 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.

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