# New molecular components of high and low affinity iron import systems in Drosophila

## TL;DR

This study identifies new iron absorption mechanisms in fruit flies, including a high-affinity system used during iron starvation.

## Contribution

The discovery of a high-affinity iron uptake system in Drosophila, including Mco4 and cytochrome b561 enzymes, is novel in animal iron biology.

## Key findings

- Mco4, a multicopper oxidase, is essential for surviving iron starvation in Drosophila.
- Cytochrome b561 enzymes Fire and Fire-like, along with Firewood, are required for normal iron absorption.
- Drosophila uses intestinal ferric reductases and a cytochrome b5 electron donor for iron uptake.

## Abstract

The high abundance and molecular versatility of iron have led to its universal presence in biological systems, yet its absorption is exceptionally challenging. Animals and yeasts use divalent metal transporters to import iron, but yeasts also employ the multicopper oxidase Fet3p for high-affinity iron uptake when iron-starved. Using long-term iron depletion in Drosophila, we identified four components involved in iron absorption: Multicopper oxidase-4 (Mco4), a Fet3p ortholog, is essential for surviving iron starvation, whereas the cytochrome b561 enzymes Fire (Ferric Iron Reductase) and Fire-like, as well as cytochrome b5 protein Firewood, are required for iron absorption under normal conditions. This study reports the presence of a high-affinity iron uptake system in an animal, a cytochrome b5 electron donor for ferric iron reduction, and intestinal ferric reductases, and provides a valuable resource for further exploration of genes involved in iron homeostasis, transport, and absorption.

Although iron is essential, its absorption is inefficient; this study uncovers distinct iron uptake strategies in Drosophila, including a previously unrecognized high-affinity system activated during iron starvation.