Fig. 1. (A) Scheme highlighting mechanisms that can increase intracellular Cu ion levels. Exposure to external agents and mis-folded peptides can cause increased levels of reactive oxygen species (ROS) leading to oxidative stress. Increased oxidative stress leads to protein oxidation releasing Cu ions from proteins and also reduces levels of glutathione (GSH) bound Cu⁺. Mutations in Cu ion transporters lead to elevated intracellular Cu ion levels. (B) Cu⁺/Cu²⁺ catalyzed Fenton reaction produces reactive hydroxyl radicals, HO˙. Cu²⁺ is reduced by cellular reductants like superoxide (O₂˙^–) and hydroascorbate (AscH^–) to complete the catalytic cycle. (C) Proposed cell-permeable Cu²⁺ chelators that alleviate oxidative stress via selective Cu²⁺ chelation.