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Fluoride Induces Neurocytotoxicity by Disrupting Lysosomal Iron Metabolism and Membrane Permeability

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Abstract

The detrimental effects of fluoride on neurotoxicity have been widely recorded, yet the detailed mechanisms underlying these effects remain unclear. This study explores lysosomal iron metabolism in fluoride-related neurotoxicity, with a focus on the Steap3/TRPML1 axis. Utilizing sodium fluoride (NaF)-treated human neuroblastoma (SH-SY5Y) and mouse hippocampal neuron (HT22) cell lines, our research demonstrates that NaF enhances the accumulation of ferrous ions (Fe2+) in these cells, disrupting lysosomal iron metabolism through the Steap3/TRPML1 axis. Notably, NaF exposure upregulated ACSL4 and downregulated GPX4, accompanied by reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity and increased malondialdehyde (MDA) levels. These changes indicate increased vulnerability to ferroptosis within neuronal cells. The iron chelator deferoxamine (DFO) mitigates this disruption. DFO binds to lysosomal Fe2+ and inhibits the Steap3/TRPML1 axis, restoring normal lysosomal iron metabolism, preventing lysosomal membrane permeabilization (LMP), and reducing neuronal cell ferroptosis. Our findings suggest that interference in lysosomal iron metabolism may mitigate fluoride-induced neurotoxicity, underscoring the critical role of the Steap3/TRPML1 axis in this pathological process.

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Data Availability

The data that support the findings of this study will be available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82360671 and 82060580), the Bingtuan Program of Science and Technology Innovation (Grant No. 2021CB046), as well as the Shihezi University International Science and Technology Cooperation Promotion Programme Project (No. GJHZ202308).

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Authors and Affiliations

  1. Department of Preventive Medicine, School of Medicine, Shihezi University, North 2nd Road, Shihezi, Xinjiang, 832000, People’s Republic of China

    Panpan Xu, Hengrui Xing, Yue Ma, Xueman Ding, Tingting Li, Yue Zhang, Li Liu, Jiaolong Ma & Qiang Niu

  2. Key Laboratory for Prevention and Control of Emerging Infectious Diseases and Public Health Security, the Xinjiang Production and Construction Corps, Shihezi, Xinjiang, People’s Republic of China

    Panpan Xu, Hengrui Xing, Yue Ma, Xueman Ding, Tingting Li, Yue Zhang, Li Liu, Jiaolong Ma & Qiang Niu

  3. Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi, Xinjiang, People’s Republic of China

    Panpan Xu, Hengrui Xing, Yue Ma, Xueman Ding, Tingting Li, Yue Zhang, Li Liu, Jiaolong Ma & Qiang Niu

  4. NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence DiseasesFirst Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, China

    Panpan Xu, Hengrui Xing, Yue Ma, Xueman Ding, Tingting Li, Yue Zhang, Li Liu, Jiaolong Ma & Qiang Niu

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Panpan Xu: Investigation, Writing–original draft. Hengrui Xing and Yue Ma: Writing–review & editing. Xueman Ding: Data curation. Tingting Li: Methodology, Yue Zhang and Li Liu: Visualization, Jiaolong Ma: Software, Validation, Qiang Niu: Resources, Conceptualization, Funding acquisition.

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Correspondence to Jiaolong Ma or Qiang Niu.

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Highlights

1. NaF exposure causes disturbed lysosomal iron metabolism by the Steap3/TRPML1 axis.

2. NaF exposure causes ferroptosis in neuronal cells.

3. DFO restored the lysosomal iron metabolism and further inhibited LMP and ferroptosis.

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Xu, P., Xing, H., Ma, Y. et al. Fluoride Induces Neurocytotoxicity by Disrupting Lysosomal Iron Metabolism and Membrane Permeability. Biol Trace Elem Res (2024). https://doi.org/10.1007/s12011-024-04226-0

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  • DOI: https://doi.org/10.1007/s12011-024-04226-0

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