Iron Homeostasis and Metabolism: Two Sides of a Coin

Iron is an ancient, essential and versatile transition metal found in almost all living organisms on Earth. This fundamental trace element is used in the synthesis of heme and iron-sulfur (Fe-S) containing proteins and other vital cofactors that are involved in respiration, redox reactions, catalysis, DNA synthesis and transcription. At the same time, the ability of iron to cycle between its oxidized, ferric (Fe³⁺) and its reduced, ferrous (Fe²⁺) state contributes to the production of free radicals that can damage biomolecules, including proteins, lipids and DNA. In particular, the regulated non-apoptotic cell death ferroptosis is driven by Fe²⁺-dependent lipid peroxidation that can be prevented by iron chelation or genetic inhibition of cellular iron uptake. Therefore, iron homeostasis must be tightly regulated to avoid iron toxicity. This review provides an overview of the origin and chemistry of iron that makes it suitable for a variety of biological functions and addresses how organisms evolved various strategies, including their scavenging and antioxidant machinery, to manage redox-associated drawbacks. Finally, key mechanisms of iron metabolism are highlighted in human diseases and model organisms, underlining the perils of dysfunctional iron handlings.