Pathological frataxin deficiency in mice causes tissue-specific alterations in iron homeostasis

Abstract

Friedreich ataxia is caused by partial frataxin deficiency due to genetic mutations. It is well established that frataxin knockout affects iron homeostasis, but the alterations caused by pathological (partial) frataxin deficiency are poorly understood. In this study, we have analyzed iron homeostasis in a mouse model presenting pathological frataxin deficiency (FXNI151F). Our results reveal tissue-specific alterations of iron regulatory proteins (IRPs). In the heart, IRP2 accumulation is observed, likely triggered by iron-sulfur deficiency, while IRP1 is decreased in the cerebellum and liver. We also found elevated iron levels in mutant mice. Accumulation was particularly pronounced in the cerebellum, where increases were already evident at 10 weeks. Hepatic accumulation was not manifested until 21 weeks and was more pronounced in females. Overall, these findings indicate that frataxin deficiency disrupts iron homeostasis in a tissue-, age-, and sex-dependent manner, and provide novel insights into the mechanisms causing these perturbations.

We thank Roser Pané for technical assistance, as well as the Proteomics and the Elemental Analysis Services from Universitat de Lleida, the Animal facilities from Universitat de Lleida, and the Lipidomics services from IRBLleida. We also thank Dr. Bruno Galy (Heidelberg) for providing samples from IRP2 KO mice. This study was supported by grant PID2020-118296RB-I00 from MCIN/AEI/10.13039/501100011033 (to J.R. and J.T.); grant PID2023-148128OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by FEDER, UE (to J.T. and E.C.); and grant PID2021-122436OB-I00 from MCIN/AEI/10.13039/501100011033/ERDF “A way to make Europe” (to M.S.), and by Association Française de l'Ataxie de Friedreich – AFAF (to F.D.).