Objective: To investigate the hepcidin-ferroportin mediated iron metabolism regulation in Friedreich´s Ataxia (FA).

Background: FA is a devastating neurogenetic disorder caused by biallelic GAA expansions in the frataxin gene. Iron accumulation is believed to contribute to disease progression in FA. Cumulative evidence identified the hormone hepdicin as the main regulator of systemic iron metabolism. Hepcidin is synthetized by the liver in condition of iron excess and binds ferroportin, the only cellular iron-exporting protein, inducing its degradation.

Method: We measured 1) systemic iron parameters including regulatory hormones (hepcidin, endogenous erythropoietin, erythroferrone) in serum/whole blood as well as 2) frataxin, ferroportin and intracellular iron metabolism parameters in PBMCs of genetically confirmed FA patients (=40) and controls (n=40). Moreover, we quantified iron content in liver, pancreas and spleen using standardized MRI techniques. We sought for correlations between the analyzed parameters and the length of the shorter GAA expansion (GAA1).

Results: FA patients displayed reduced serum iron levels and transferrin saturation compared to controls; serum ferritin and mean corpuscular volume showed a significant inverse correlation with the GAA1 repeat length in FA. Serum values of iron regulatory hormones were comparable in FA and controls. MRI R2* mapping demonstrated lower iron storages in the liver and spleen of FA. Liver and spleen R2* values showed a significant inverse correlation with the GAA1 repeat length. FA PBMCs displayed an upregulation of transferrin receptor and downregulation of ferritin, hepcidin and lipocalin-2. Moreover, the expression of HIF1α was downregulated in FA PBMCs and directly correlated with the frataxin levels.

Conclusion: Collectively, our data show that FA features an iron starvation signature, both at a systemic and cellular level, whose degree correlates with the underlying genetic severity. We highlight a disturbance of the HIF1α as a novel pathophysiological mechanism deserving further investigations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/systemic-and-intracellular-iron-starvation-response-in-friedreichs-ataxia/