ER stress promoted MAMs formation and ER-Mito Ca²⁺ transfer: implication for fluoride-induced hippocampal neuronal injury and cognitive deficits in mice.

Authors

Siman Lin, LuYang Cao, Yuzhe Zhou, Shengdan Liu, Yue Yan, Qiwei Zhang, Quan Yuan, Yufei Gao, Ge Du, Jun Hu, Dongmei Wang, Hua Fan

Published in

Chemico-biological interactions. Volume 437. Pages 112252. Jul 14, 2026. Epub Jul 14, 2026.

Abstract

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are crucial contributors to the pathophysiological progression of fluorosis. Recently, the disturbance of the linked membrane microdomains between ER and mitochondria (ER-derived mitochondria-associated membranes, MAMs) has been implicated in fluoride toxicity. Therefore, this study aims to elucidate the involvement of MAMs in fluoride neurotoxicity, specifically by examining how MAMs regulate ER-mitochondria crosstalk and contribute to subsequent hippocampal damage and cognitive dysfunction. In the current investigation, our experimental results observed significant ER stress and aberrant MAMs formation as well as the upregulation of the IP3R1/Grp75/VDAC1 calcium channel proteins in fluoride-treated hippocampal HT-22 neurons and mouse hippocampus. Enhancement of ER-mitochondrial Ca²⁺ transfer triggered mitochondrial Ca²⁺ overload, thereby accelerating mtROS production and the dissipation of mitochondrial membrane potential (MMP), leading to Cyt c release-mediated apoptosis in fluoride-treated mouse hippocampal HT-22 neurons. Conversely, uncoupling the IP3R1/Grp75/VDAC1 calcium channel by silencing Grp75 effectively blocked fluoride-induced ER-mitochondrial Ca²⁺ transfer and mitochondrial Ca²⁺ overload-mediated hippocampal neuronal apoptosis. Furthermore, ER stress inhibitor 4-phenylbutyric acid (4-PBA) substantially attenuated fluoride-induced enhancement of MAMs formation and IP3R1/Grp75/VDAC1 expression as well as mitochondrial Ca²⁺ overload-mediated apoptotic hippocampal neuron. Importantly, pretreatment with 4-PBA proved highly effective in reversing fluoride-induced deficits, including neuronal injury, synaptic dysfunction, and cognitive impairment. Collectively, our data suggested a previously unrecognized mechanism underlying fluoride-induced hippocampal neuronal death that ER stress enhanced MAMs formation and ER-mitochondrial Ca²⁺ transfer via the IP3R1/Grp75/VDAC1 complex and provided a potential therapeutic target for the treatment of fluoride-associated neurotoxicity and neurobehavioral disorders.

PMID:
42447516
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.

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