2. Academic Validation
  3. PRKAA1 induces aberrant mitophagy in a PINK1/Parkin-dependent manner, contributing to fluoride-induced developmental neurotoxicity

PRKAA1 induces aberrant mitophagy in a PINK1/Parkin-dependent manner, contributing to fluoride-induced developmental neurotoxicity

  • Ecotoxicol Environ Saf. 2023 Mar 14;255:114772. doi: 10.1016/j.ecoenv.2023.114772.
Yanling Tang 1,  Jingjing Zhang 1,  Zeyu Hu 1,  Wanjing Xu 1,  Panpan Xu 1,  Yue Ma 1,  Hengrui Xing 1,  Qiang Niu 2
Affiliations

Affiliations

  • 1 Department of Preventive Medicine, School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; Key Laboratory of Preventive Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (First Affiliated Hospital, School of Medicine, Shihezi University), People's Republic of China.
  • 2 Department of Preventive Medicine, School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; Key Laboratory of Preventive Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (First Affiliated Hospital, School of Medicine, Shihezi University), People's Republic of China. Electronic address: niuqiang1022@163.com.
PMID: 36924562 DOI: 10.1016/j.ecoenv.2023.114772
Abstract

Chronic fluoride exposure can cause developmental neurotoxicity, however the precise mechanisms remain unclear. To explore the mechanism of Mitophagy in fluoride-induced developmental neurotoxicity, specifically focusing on PRKAA1 in regulating the PINK1/Parkin pathway, we established a Sprage Dawley rat model with continuous sodium fluoride (NaF) exposure and an NaF-treated SH-SY5Y cell model. We found that NaF exposure increased the levels of LC3-Ⅱ and p62, impaired autophagic degradation, and subsequently blocked autophagic flux. Additionally, NaF exposure increased the expression of PINK1, Parkin, TOMM-20, and Cyt C and cleaved PARP in vivo and in vitro, indicating NaF promotes Mitophagy and neuronal Apoptosis. Meanwhile, phosphoproteomics and western blot analysis showed that NaF treatment enhanced PRKAA1 phosphorylation. Remarkably, the application of both 3-methyladenosine (3-MA; Autophagy Inhibitor) and dorsomorphin (DM; AMPK Inhibitor) suppressed NaF-induced neuronal Apoptosis by restoring aberrant Mitophagy. In addition, 3-MA attenuated an increase in p62 protein levels and NaF-induced autophagic degradation. Collectively, our findings indicated that NaF causes aberrant Mitophagy via PRKAA1 in a PINK1/Parkin-dependent manner, which triggers neuronal Apoptosis. Thus, regulating PRKAA1-activated PINK1/Parkin-dependent Mitophagy may be a potential treatment for NaF-induced developmental neurotoxicity.

Keywords

Aberrant mitophagy; Autophagic degradation; Developmental neurotoxicity; Fluoride; Neuronal apoptosis; PRKAA1.

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