Double-edge sword roles of iron in driving energy production versus instigating ferroptosis

Iron is vital for many physiological functions, including energy production, and dysregulated iron homeostasis underlies a number of pathologies. Ferroptosis is a recently recognized form of regulated cell death that is characterized by iron dependency and lipid peroxidation, and this process has been reported to be involved in multiple diseases. The mechanisms underlying ferroptosis are complex, and involve both well-described pathways (including the iron-induced Fenton reaction, impaired antioxidant capacity, and mitochondrial dysfunction) and novel interactions linked to cellular energy production. In this review, we examine the contribution of iron to diverse metabolic activities and their relationship to ferroptosis. There is an emphasis on the role of iron in driving energy production and its link to ferroptosis under both physiological and pathological conditions. In conclusion, excess reactive oxygen species production driven by disordered iron metabolism, which induces Fenton reaction and/or impairs mitochondrial function and energy metabolism, is a key inducer of ferroptosis.

Automated summary

Iron is crucial for energy production and dysregulated iron homeostasis is the basis of many pathologies. Ferroptosis, an iron-dependent and lipid peroxidation-driven form of regulated cell death, has been implicated in various diseases. The mechanisms of ferroptosis are complex, involving well-established pathways as well as novel interactions related to cellular energy production. This review explores the contribution of iron to diverse metabolic activities and its connection to ferroptosis, emphasizing its role in driving energy production under both normal and pathological conditions.