Fig. 2

Downstream effectors of iron and other metal ions. a The import of iron mainly depends on TfR1-mediated endocytosis or DMT1, while FPN1 is the sole known exporter of iron. The import of copper mainly depends on CTR1, which can be upregulated by Cu(I)-GSH. DMT1 also participates in the import of copper. The export of copper is mediated by ATP7A/7B with the assistance of Atox1. As a copper-binding protein, Cp also functions as a ferroxidase to convert toxic ferrous iron into nontoxic ferric iron. Excessive copper leads to the aggregation of lipoylated proteins and the loss of iron-sulfur cluster proteins, resulting in cuproptosis. The import of manganese relies on the DAT, ZIP8, Tf/TfR system, or DMT1, while the export of manganese depends on SLC30A70 and FPN1. Manganese can activate ATM/ p53, which regulates cell cycles and reduces DNA damage. In the mitochondria, Mn²⁺ can bind to intermediate products of the TCA cycle and promote the generation of ROS, while Mn³⁺ can help SOD2 to mitigate the generation of ROS and prevent cells from undergoing apoptosis. ZIPs are the main channels for transporting zinc into the cytoplasm from extracellular or ER, while ZnTs are responsible for transporting zinc out of the cytoplasm or into synaptic vesicles, lysosomes, and Golgi. Both ferrous iron and copper can promote the Fenton reaction, leading to the generation of ROS and initiating oxidative stress. However, zinc can compete with copper or iron, thereby preventing the generation of ROS. Both excessive Fe²⁺ and Mn²⁺ iron can lead to the accumulation of lipid peroxidation and trigger ferroptosis, which can be inhibited by copper chelators. b High levels of metal ions, including iron, manganese, copper, and zinc have been found to be involved in cell senescence. This process can be rescued by the iron chelator DFO. c Excessive metal ions such as iron, manganese, copper, and zinc can also activate microglia and astrocytes to release pro-inflammatory cytokines, thereby triggering neuroinflammation. This figure was created with BioRender.com/j25f189