1. Academic Validation
  2. Fluoride impairs mitochondrial translation by targeting miR-221-3p/c-Fos/RMND1 axis contributing to neurodevelopment defects

Fluoride impairs mitochondrial translation by targeting miR-221-3p/c-Fos/RMND1 axis contributing to neurodevelopment defects

  • Sci Total Environ. 2023 Jan 21;869:161738. doi: 10.1016/j.scitotenv.2023.161738.
Dongjie Li 1 Qian Zhao 1 Li Xie 1 Chenxi Wang 1 Zhiyuan Tian 1 Huayang Tang 1 Tao Xia 1 Aiguo Wang 2
Affiliations

Affiliations

  • 1 Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei 430030, People's Republic of China; Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei 430030, People's Republic of China.
  • 2 Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei 430030, People's Republic of China; Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei 430030, People's Republic of China. Electronic address: wangaiguo@mails.tjmu.edu.cn.
Abstract

Evidence suggests that fluoride-induced neurodevelopment damage is linked to mitochondrial disorder, yet the detailed mechanism remains unclear. A cohort of Sprague-Dawley rats developmentally exposed to sodium fluoride (NaF) was established to simulate actual exposure of human beings. Using high-input proteomics and small RNA Sequencing technology in rat hippocampus, we found mitochondrial translation as the most striking enriched biological process after NaF treatment, which involves the differentially expressed Required Meiotic Nuclear Division 1 homolog (RMND1) and neural-specific miR-221-3p. Further experiments in vivo and in vitro neuroendocrine pheochromocytoma (PC12) cells demonstrated that NaF impaired mitochondrial translation and function, as shown by declined mitochondrial membrane potential and inhibited expression of mitochondrial translation factors, mitochondrial translation products, and OXPHOS complexes, which was concomitant with decreased RMND1 and transcription factor c-Fos in mRNA and proteins as well as elevated miR-221-3p. Notably, RMND1 overexpression alleviated the NaF-elicited mitochondrial translation impairment by up-regulating translation factors, but not vice versa. Interestingly, ChIP-qPCR confirmed that c-Fos specifically controls the RMND1 transcription through direct binding with Rmnd1 promotor. Interference of gene expression verified c-Fos as an upstream positive regulator of RMND1, implicating in fluoride-caused mitochondrial translation impairment. Furthermore, dual-luciferase reporter assay evidenced that miR-221-3p targets c-Fos by binding its 3' untranslated region. By modulating the miR-221-3p expression, we identified miR-221-3p as a critical negative regulator of c-Fos. More importantly, we proved that miR-221-3p inhibitor improved mitochondrial translation and mitochondrial function to combat NaF neurotoxicity via activating the c-Fos/RMND1 axis, whereas miR-221-3p mimic tended towards opposite effects. Collectively, our data suggest fluoride impairs mitochondrial translation by dysregulating the miR-221-3p/c-Fos/RMND1 axis to trigger mitochondrial dysfunction, leading to neuronal death and neurodevelopment defects.

Keywords

Fluoride; Mitochondrial dysfunction; Mitochondrial translation; Neurodevelopment defects; miR-221-3p/c-Fos/RMND1 axis.

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