Insight of the role of mitochondrial iron homeostasis in insulin resistance

Insulin resistance (IR) is characterized by impaired insulin responsiveness in metabolic tissues, leading to defective glucose disposal, dysregulated lipid metabolism, and compensatory hyperinsulinemia. Mitochondrial iron homeostasis is crucial for cellular metabolism, oxidative phosphorylation (OXPHOS), and redox balance. Dysregulation of mitochondrial iron contributes to IR by impairing electron transport chain (ETC) function, increasing reactive oxygen species (ROS), and disrupting insulin signaling pathways. Excess mitochondrial iron leads to oxidative stress through the Fenton reaction, promoting lipid peroxidation, mitochondrial dysfunction, and inflammation, all of which exacerbate metabolic disorders. Additionally, mitochondrial iron overload affects iron-sulfur (Fe-S) cluster biosynthesis, mitochondrial dynamics, and energy metabolism, further impairing glucose homeostasis. Emerging evidence suggests that mitochondrial iron dysregulation plays a pivotal role in the pathogenesis of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Future research should focus on the molecular mechanisms governing mitochondrial iron transport and utilization, as well as its interaction with key metabolic pathways, to better understand its role in disease progression and potential therapeutic implications.