Fig. 4

Iron dysregulation in the lysosome and mitochondria of PD. The Tf-TfR system mediates the uptake of Fe³⁺ and DMT1 mediates the uptake of Fe²⁺, which are the two major pathways for the neuronal iron influx. FPN1 is responsible for exporting Fe²⁺ with the help of APP, Cp, or hephaestin (Hep). Endosome contains abundant Fe³⁺ through Tf-TfR1 uptake, while autophagosome contains ferritin bound to NCOA4, which are the main source of iron in lysosomes. In the acidic and reducing environment of the lysosome, Fe³⁺ is reduced to Fe²⁺ and released into the cytosolic through DMT1, TRPML1, Nramp1, or TPCNs. The overexpression of TFEB can upregulate the synthesis of TfR1 through the FBXL5-IRP2 pathway and increase the localization of TfR1 in lysosomes, thereby facilitating the import and temporary storage of iron in lysosomes. VDAC, Tf-TfR2, and DMT1, all of which are located on the outer mitochondrial membrane, are responsible for the iron transport across the outer mitochondrial membrane. The transport of iron across the inner mitochondrial membrane is mediated by Mfrn1/2. In the mitochondrial matrix, iron is stored in FtMt. Rotenone induces an increased level of Tf, while MPTP or 6-OHDA induces increased levels of VDAC in mitochondria. Additionally, excessive iron induces the generation of ROS and lipid peroxidation through the Fenton reaction, further leading to ferroptosis. However, overexpression of TFEB or FtMt has the ability to suppress α-synuclein aggregation and decrease the cellular labile iron pool. All these processes contribute to the nigral dopaminergic neuronal death. This figure was created with BioRender.com/u48z218