Petit Floriane, Drecourt Anthony, Dussiot Michaël, Zangarelli Coralie, Hermine Olivier, Munnich Arnold, Rötig Agnès
UMR1163, Institut Imagine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Laboratory of Excellence GR-Ex, Institut Imagine, Paris, France; and.
Blood. 2021 Apr 15;137(15):2090-2102. doi: 10.1182/blood.2020006987.
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.
弗里德赖希共济失调（FRDA）是一种常见的常染色体隐性疾病，由编码线粒体蛋白酵母铁硫蛋白的FXN基因中的GAA重复序列扩增引起，该蛋白参与铁硫簇（ISC）生物合成。由此导致的酵母铁硫蛋白缺乏会影响含ISC的蛋白质，并导致铁在FRDA患者的大脑和心脏中积累。在此，我们报告了FRDA成纤维细胞中异常的细胞铁稳态，这会导致细胞质和线粒体中大量铁过载。我们观察到膜转铁蛋白受体1（TfR1）积累、TfR1内吞作用增加以及Tf循环延迟，将此归因于TfR1棕榈酰化受损。研究表明，酵母铁硫蛋白缺乏会降低用于TfR1棕榈酰化的辅酶A（CoA）可用性。最后，我们证明青蒿琥酯、CoA和二氯乙酸可改善TfR1棕榈酰化并减少铁过载，为基于证据的FRDA治疗策略铺平了道路，该策略可在TfR1棕榈酰化这一可操作层面上发挥作用。
