Aluminum maltolate triggers ferroptosis in neurons: Mechanism of action.

Aluminum (Al), a neurotoxic element, can induce Alzheimer's disease (AD) via triggering neuronal death. Ferroptosis is a new type of programmed cell death related to neurological diseases. Unfortunately, its role in aluminum-induced neuronal death remains completely unclear. This study aimed to investigate whether ferroptosis is involved in neuronal death in response to aluminum exposure as well as its underlying mechanism. In this study, rat adrenal pheochromocytoma (PC12) cells were treated with 200 mu M aluminum maltolate (Al(mal)(3)) for 24 h, and related biochemical indicators were assessed to determine whether ferroptosis was induced by aluminum in neurons. Then, the potential mechanism was explored by detecting of these genes and proteins associated with ferroptosis after adding ferroptosis-specific agonist Erastin (5 mu M) and antagonist Ferrostatin-1 (Fer-1) (5 mu M). The experimental results demonstrated that aluminum exposure significantly increased the death of PC12 cells and caused specific mitochondrial pathological changes of ferroptosis in PC12 cells. Further research confirmed that ferroptosis was triggered by aluminum in PC12 cells by means of activating the oxidative damage signaling pathway, which was displayed as inhibition of the cysteine/glutamate antiporter system (system Xc(-)), causing the depletion of cellular glutathione (GSH) and inactivation of glutathione peroxidase (GSH-PX) eventually lead to accumulation of reactive oxygen species (ROS). Taken together, ferroptosis was a means of neuronal death induced by aluminum and oxidative damage may be its underlying mechanism, which also provided some new clues to potential target for the intervention and therapy of AD.