Iron Deficiency in Drosophila melanogaster Glial Cells Impacts Behavior Through Altered Mitochondrial Dynamics

Iron deficiency (ID) is the most common micronutrient deficiency globally. ID in pre- and post-natal periods has been associated with impaired neurological development and altered behavior, which may persist despite iron supplementation. However, the neurobiological changes responsible for these findings have not been fully identified yet. Here, we develop an invertebrate experimental model using Drosophila melanogaster to study the impact of ID on glial cells. ID induced by dietary deferoxamine altered locomotor activity in adult flies. Glial-specific downregulation of the iron transporter Malvolio (Mvl) resulted in reduced locomotion, an effect prevented by iron supplementation in the fly medium. We confirmed that Mvl downregulation led to ID in the brain, where Mvl is partially expressed. Interestingly, Mvl reduction in ensheathing glia replicated locomotor activity deficits, which suggests that this glial subpopulation is particularly sensitive to iron levels. Mvl downregulation also altered mitochondrial morphology and size, in correlation with altered expression of mitochondrial fission and fusion genes, and mitochondrial electron transport chain complex genes. These results suggest that glial ID impairs normal mitochondrial dynamics and impacts energy production. Additionally, glial overexpression of mitochondrial ferritin, Fer3HCH, known to induce ID in the cytosol and mitochondria, also impaired locomotor activity, which highlights the importance of iron availability in both compartments. These findings demonstrate, for the first time, the importance of iron availability in Drosophila glial cells and its impact on behavior and mitochondrial dynamics. Most importantly, the Drosophila model proves useful in unveiling previously unknown cellular and molecular mechanisms associated with ID in glial cells.