Storage and transport of labile iron is mediated by lysosomes in axons and dendrites of hippocampal neurons

Abstract Iron dyshomeostasis in neurons, involving iron accumulation and abnormal redox balance, is implicated in neurodegeneration. In particular, labile iron, a highly reactive pool of intracellular iron, plays a prominent role in iron-induced neurological damage. However, the mechanisms governing the detoxification and transport of labile iron within neurons are not fully understood. This study investigates the storage and transport of labile ferrous iron Fe(II) in cultured primary rat hippocampal neurons. Iron distribution was studied using live cell fluorescence microscopy with a selective labile Fe(II) fluorescent dye, and synchrotron X-ray fluorescence microscopy (SXRF) for total iron distribution. Fluorescent labeling of the axon initial segment and of lysosomes allowed iron distribution to be correlated with these subcellular compartments. The results show that labile Fe(II) is stored in lysosomes within somas, axons, and dendrites and that lysosomal labile Fe(II) is transported retrogradely and anterogradely along axons and dendrites. In addition, SXRF imaging of total iron confirms iron uptake and iron distribution in the form of iron-rich dots in the soma and neurites. These results suggest that after exposure to Fe(II), labile Fe(II) is stored in lysosomes and can be transported along dendrites and axons. These storage and transport mechanisms could be associated with the detoxification of reactive Fe(II) in lysosomes, which protects cellular structures from oxidative stress. They could also be associated with the metabolic functions of iron in the soma, axons, and dendrites. In this case, easily exchangeable Fe(II) is transported in lysosomes to the neuronal compartments where iron is required.