Ca2+ transfer via enhancing ER-Mito coupling contributed to BDE-47- induced hippocampal neuronal necroptosis and cognitive dysfunction

2,2,4,4-Tetrabromodiphenyl ether (BDE-47), a ubiquitous environmental pollutant, has gained increasing attention due to its high level in biological samples and potential neurotoxicity. Recent studies have indicated that the receptor interacting protein kinase 1 (RIPK1)-mediated necroptosis is implicated in BDE-47 cytotoxicity. However, little is known about the underlying mechanism and whether the necroptosis participates in BDE-47-induced neuronal injury and cognitive impairment. Our results indicated that exposure to BDE-47 triggered RIPK1-dependent neuronal necroptosis in mice hippocampi and HT-22 mouse hippocampal neurons. Necrostain-1 (Nec-1), a specific RIPK1 inhibitor, suppressed the RIPK1/RIPK3/mixed lineage kinase-like domain protein (MLKL) signaling and rescued neuronal survival in BDE-47-treated HT-22 neurons. Mechanically, increased mitochondrial Ca²⁺ influx precipitated the opening of the mitochondrial permeability transition pore (mPTP), leading to occurrence of hippocampal neuronal necroptosis under BDE-47 stress. BDE-47 exposure induced excessive mitochondria-associated endoplasmic reticulum membranes (MAMs) formation and promoted ER-to-mitochondria Ca²⁺ transfer, while diminishing ER-mitochondrial contacts by Glucose-regulated protein 75 (Grp75)-deficiency remarkably prevented mitochondria Ca²⁺ overload and opening of mPTP as well as neuronal necroptosis. Notably, Nec-1 pre-treatment could substantially mitigate neuronal/synaptic damage and cognitive impairment in BDE-47-exposed mice. Collectively, these data suggest that BDE-47 exposure intensified endoplasmic reticulum (ER)-mitochondrial (Mito) contact and facilitated Ca²⁺ transfer from ER towards mitochondria, resulting in mPTP opening-mediated hippocampal neuronal necroptosis and subsequent cognitive dysfunction. Our study shed new light on the mechanisms underlying BDE-47 neurotoxicity and provided a novel therapeutic strategy through targeting RIPK1 kinase activity.