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

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.