The role of redox-active iron, copper, manganese, and redox-inactive zinc in toxicity, oxidative stress, and human diseases
Abstract
Given the key importance played by the redox-active metals iron (Fe), copper (Cu), and manganese (Mn) in vital cellular processes, such as DNA synthesis, oxidative phosphorylation, the detoxification of reactive oxygen species (ROS), and angiogenesis, it is not surprising that their dysregulation plays a causative role in many human diseases. The same applies to redox-inactive zinc (Zn), which is involved in numerous biological functions, and serves as a structural element, a catalyst, and a participant in both intracellular and intercellular signaling and in maintaining immune system function. An imbalance in redox active (Fe, Cu, Mn) or redox inactive (Zn) metal ions, whether in excess or deficiency, is harmful and may disrupt the structural, regulatory, and catalytic roles of various antioxidant enzymes (superoxide dismutases (SODs), catalase (CAT), glutathione peroxidases (GPxs)), proteins, receptors, transporters, alter sulfhydryl homeostasis, generate high levels of ROS (e.g., hydroxyl radicals by the Fenton reaction), initiate lipid peroxidation, cause DNA damage, and lead to cell death via mechanisms such as ferroptosis, cuproptosis, cellular senescence, or inflammation. Maintaining redox homeostasis is essential for regulating numerous cellular signaling pathways. Redox-sensitive signaling pathways, such as the nuclear factor kappa B (NF-κB), mitogen-activated protein kinase kinase (MAPK), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, form an…
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