Limiting intestinal iron absorption rescues glial defects and extends lifespan in a Drosophila model of Friedreich's ataxia

Friedreich ataxia (FRDA) is a neurodegenerative and cardiac disease caused by GAA repeat expansions within the first intron of the FXN gene, leading to reduced frataxin expression. Frataxin is involved in iron sulfur cluster (ISC) biosynthesis, and its deficiency results in multiple cellular dysfunctions, including mitochondrial iron overload. Although altered iron homeostasis has been reported in several frataxin-deficient models and in FRDA patients, its contribution to disease progression remains debated. Here, we used a GAA expansion-based Drosophila model of FRDA, termed fh-GAAs, to investigate the impact of reducing intestinal iron absorption on disease progression. We first found that iron accumulation was tissue-specific and predominantly affected the central nervous system. Furthermore, glial cells were affected more severely than neurons, suggesting an increased vulnerability of glia to frataxin deficiency. Reducing intestinal iron uptake, either through treatment with bathophenanthroline disulfonic acid (BPS), an extracellular iron chelator, or by gut-specific silencing of the gene encoding the iron transporter Malvolio, nearly doubled fly survival. BPS treatment also improved sensitivity to dietary iron, enhanced locomotor performance, fully restored normal brain size, and prevented glial alterations. Altogether, our findings identify glial cells as early and preferential targets of frataxin deficiency in an iron-dependent manner and support the in vivo relevance of intestinal iron uptake as a potential modulator of disease severity in FRDA.