Defective palmitoylation of transferrin receptor triggers iron overload in Friedreich ataxia fibroblasts - Université Paris Cité Access content directly
Journal Articles Blood Year : 2021

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.

Dates and versions

hal-03241848 , version 1 (29-05-2021)

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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, 2021, 137 (15), pp.2090-2102. ⟨10.1182/blood.2020006987⟩. ⟨hal-03241848⟩

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