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

## TL;DR

This study shows that partial frataxin deficiency in mice leads to tissue-specific changes in iron levels and regulation, offering new insights into Friedreich ataxia.

## Contribution

The study reveals tissue-, age-, and sex-dependent disruptions in iron homeostasis caused by pathological frataxin deficiency in a mouse model.

## Key findings

- Heart tissue shows IRP2 accumulation and decreased ferritin in FXNI151F mice.
- Cerebellum and liver exhibit iron accumulation and reduced IRP1 content.
- Iron accumulation in the cerebellum occurs earlier and is more pronounced in females.

## 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.

•FXNI151F mice present partial frataxin deficiency, as Friedreich ataxia patients•FXNI151F mice show tissue and sex-specific alterations in iron homeostasis•Heart presents IRP2 accumulation, Tfrc induction, and ferritin decrease•Cerebellum and liver present iron accumulation and IRP1 content decrease

FXNI151F mice present partial frataxin deficiency, as Friedreich ataxia patients

FXNI151F mice show tissue and sex-specific alterations in iron homeostasis

Heart presents IRP2 accumulation, Tfrc induction, and ferritin decrease

Cerebellum and liver present iron accumulation and IRP1 content decrease

Health sciences