Aluminum Exposure Impairs Electrochemically Measured Vesicular Storage and Exocytosis via Iron Homeostasis Dysregulation

Widespread human exposure to aluminum (Al) has raised increasing concerns about its effects on neuronal functions since Al³⁺ can cross the blood-brain barrier and accumulate in neuronal cells, especially considering its ionic similarity to ferric iron (Fe³⁺), a metal strongly associated with neurodegenerative diseases. In this study, we demonstrate that Al³⁺ affects vesicles in an iron-status-dependent manner in pheochromocytoma (PC12) cells, causing distinct changes under iron-normal, deficient, and overloaded conditions. Al³⁺ competes with Fe³⁺ for transferrin binding and enters cells via transferrin receptor (TfR)-mediated endocytosis, ultimately leading to cellular iron deficiency. This disruption alters dopamine-related proteins and molecular pathways, impairing exocytotic dynamics and reducing the average vesicular transmitter storage. When iron level is overloaded, TfR expression is downregulated to avoid Al³⁺ affecting vesicles. However, supplementation with ferric ammonium citrate (FAC) fails to reverse Al³⁺-induced iron deficiency due to Al³⁺ simultaneously upregulating TfR, allowing excess Fe³⁺ to further decrease neurotransmitter release. Furthermore, deferoxamine (DFOM), an Fe chelator, destabilizes exocytotic fusion pores, suggesting a potential drawback of chelation therapy. These findings highlight iron dysregulation as a key pathway through which Al³⁺ impairs vesicular function, providing a new insight into how metal ion interactions modulate neurotransmission.