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

Abstract : Abstract Friedreich ataxia (FRDA) is a frequent autosomal recessive disease caused by a GAA repeat expansion in the FXN gene encoding frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biogenesis. Resulting frataxin deficiency affects ISC-containing proteins and causes iron to accumulate in the brain and heart of FRDA patients. Here we report on abnormal cellular iron homeostasis in FRDA fibroblasts inducing a massive iron overload in cytosol and mitochondria. We observe membrane transferrin receptor 1 (TfR1) accumulation, increased TfR1 endocytosis, and delayed Tf 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.
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https://hal-univ-paris.archives-ouvertes.fr/hal-03241848
Contributor : Hal Paris Diderot <>
Submitted on : Saturday, May 29, 2021 - 12:21:42 PM
Last modification on : Wednesday, June 2, 2021 - 4:27:36 PM

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Floriane Petit, Anthony Drecourt, Michaël Dussiot, Coralie Zangarelli, Olivier Hermine, et al.. Defective palmitoylation of transferrin receptor triggers iron overload in Friedreich ataxia fibroblasts. Blood, American Society of Hematology, 2021, 137 (15), pp.2090-2102. ⟨10.1182/blood.2020006987⟩. ⟨hal-03241848⟩

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