Mechanism and regulation of iron uptake and efflux in primary hippocampal neurons
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Iron is an essential cofactor for normal neuronal development and function. Both iron deficiency and accumulation are associated with neuronal dysfunction or neurodegeneration. Therefore, iron homeostasis needs to be tightly regulated. This delicate balance is maintained through iron uptake, efflux and storage. Although the expression of proteins involved in these three processes has been detected in neurons, the detailed molecular mechanisms that supported by these proteins have not been well characterized. In this thesis, I used primary hippocampal neurons to identify the expression of key proteins that mediated neuronal iron uptake and efflux; also, I investigated the kinetics supported by these proteins. First, I dissected the molecular mechanisms of iron uptake in neurons using either transferrin bound iron or non-transferrin bound iron as the potential physiological substrates. Ferrous iron transporter Zip8, DMT1 and ferrireductase Steap2 play important roles in mediating both ferrous and ferric iron uptake. Next, I demonstrated the mechanisms of iron efflux from primary neurons, which requires a cooperation between ferroxidase Hp with iron exporter Fpn. Furthermore, I presented evidence that suggested neuronal development, intracellular iron status, as well as neuronal activity, can modulate iron uptake and/or efflux. These regulatory mechanisms diagram a well-controlled neuronal iron homeostasis under physiological conditions.