https://www.sciencedirect.com/science/a ... 1325015325
PFPC Commentary:Abstract
Fluoride exposure poses multi-organ toxicity, including skeletal fluorosis, dental fluorosis, neuroinflammation, and cognitive deficits. While fluoride-induced neurotoxicity is linked to mitochondrial dysfunction-particularly via disrupted mitochondrial translation-the mechanistic interplay between translational impairment, neuroinflammation, and cognitive decline remains poorly defined. Here, integrated proteomic and functional analyses revealed that fluoride upregulates mitochondrial ribosomal protein L15 (MRPL15) through its upstream transcription factor CCAAT/enhancer-binding protein-α (C/EBPα) in both in vivo and in vitro models. This dysregulation perturbed mitochondrial translation fidelity, culminating in mitochondrial reactive oxygen species (mtROS) overproduction. Elevated mtROS activated the NLRP3 inflammasome, triggering pyroptotic cell death and subsequent hippocampal-dependent cognitive impairment. Importantly, the natural compound curcumin (CUR) attenuated fluoride neurotoxicity by enhancing mitochondrial bioenergetics and suppressing the mtROS/NLRP3-pyroptosis axis. Our findings establish mitochondrial translation disruption as a novel mechanism underlying fluoride-induced neuroinflammation and cognitive deficits, urging a critical re-evaluation of fluoride safety thresholds in environmental health policies.
- The NLRP3 inflammasome is directly regulated by the G protein Gq/11 (Kong et al., 2024).
- The NLRP3 pathway is negatively regulated by thyroid hormone (T3) (e.g. Dong et al., 2018; Vargas et al., 2017; Mokhtari et al., 2021).
- Numerous previous studies have shown how fluoride activates the NLRP3 pathway (e.g. Chen et al., 2024; Li et al., 2024; Zhang et al., 2024). Organic fluoride compounds, such as sevoflurane or PFAS, also affect the NRLP3 pathway (e.g. Qin et al., 2022; Shi et al., 2024; Wang et al., 2023).
Multiple studies have demonstrated that fluoride exposure activates the NLRP3 pathway in various tissues (Chen 2024; Li 2024; Zhang 2024), and similar activation has been observed for organic fluoride compounds, such as sevoflurane or PFAS compounds (Han et al., 2024; Qin 2022; Shi 2024; Wang 2023).
This occurs via Gq/11 signaling, as Gq/11 regulates NLRP3 inflammasome activation (Kong 2024). Gq/11 signaling is tightly linked to mitochondrial translation and biogenesis control (Benincá et al., 2014).
In turn, NLRP3 inflammasome activity is downregulated by T3, the biologically active thyroid hormone (Mokhtari 2021, Dong et al., 2018; Vargas et al., 2017).
Together, these data provide a coherent physiological framework in which T3-mediated mitochondrial regulation and Gq/11 signaling represent plausible upstream activators of the mtROS–NLRP3 axis described in the paper, situating fluoride effects within known thyroidal and GPCR-dependent signaling pathways rather than as an isolated toxicological mechanism.
This is another example of fluoride being functionally antagonistic to T3 regulation - a local and tissue-specific fluoride-iodine antagonism.
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"Results indicate that PGF2alpha inhibits adipocyte differentiation via a G alpha q-Ca2+-calcineurin-dependent signaling pathway that acts to block expression of PPARgamma and C/EBPalpha by a mechanism that appears to involves an HDAC-sensitive step."