Copper homeostasis in eukaryotes: Teetering on a tightrope

The transition metal copper is an essential trace element for both prokaryotes and eukaryotes. However, intracellular free copper has to be strictly limited due to its toxic side effects, not least the generation of reactive oxygen species (ROS) via redox cycling. Thus, all organisms have sophisticated copper homeostasis mechanisms that regulate uptake, distribution, sequestration and export of copper. From insects to mammals, metal-responsive transcription factor (MTF-1), a zinc finger transcription factor, controls expression of metallothioneins and other components involved in heavy metal homeostasis. In the fruit fly Drosophila, MTF-1 paradoxically acts as an activator under both high and low copper concentrations. Namely, under high copper conditions, MTF-1 activates metallothioneins in order to protect the cell, while under low copper conditions MTF-1 activates the copper importer Ctr1B in order to acquire scarce copper from the surroundings. This review highlights the current knowledge of copper homeostasis in eukaryotes with a focus on Drosophila and the role of MTF-1.