2026: ER stress promoted MAMs formation and ER-Mito Ca2+ transfer: implication for fluoride-induced neuronal injury

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Lin S, Cao L, Zhou Y, Liu S, Yan Y, Zhang Q, Yuan Q, Gao Y, Du G, Hu J, Wang D, Fan H - "ER stress promoted MAMs formation and ER-Mito Ca2+ transfer: implication for fluoride-induced hippocampal neuronal injury and cognitive deficits in mice" Chem Biol Interact 437:112252 (2026)
https://doi.org/10.1016/j.cbi.2026.112252

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.

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PFPC Commentary:

Here we have yet another paper in which the authors describe a canonical downstream Gq/11 signalling pathway without recognizing or naming it as such. The IP3R1/Grp75/VDAC1 complex constitutes the principal conduit for Ca2+ transfer from the endoplasmic reticulum to mitochondria following activation of the Gq/11-PLCβ-IP3 pathway:

Gq/11 activation -> PLCβ activation -> PIP2 hydrolysis -> IP3 production -> IP3R1 opening -> ER Ca2+ release -> transfer through the IP3R1/Grp75/VDAC1 complex into mitochondria.

The mitochondrial Ca2+ overload, increased mitochondrial ROS production, loss of mitochondrial membrane potential, cytochrome c release, and apoptosis reported in this study are therefore fully consistent with excessive or dysregulated Gq/11-PLCβ-IP3 signalling. However, the authors examined only the downstream ER-mitochondrial Ca2+ transfer machinery. They did not directly assess Gq/11 activation, PLCβ activity, PIP2 hydrolysis, or IP3 production. The study therefore identifies a mechanism that lies directly within a canonical Gq/11-linked signalling cascade, but fails to investigate or acknowledge its likely upstream signalling context.