2. Academic Validation
  3. Cobalt induces neurodegeneration through FTO-triggered autophagy impairment by targeting TSC1 in an m6A-YTHDF2-dependent manner

Cobalt induces neurodegeneration through FTO-triggered autophagy impairment by targeting TSC1 in an m6A-YTHDF2-dependent manner

  • J Hazard Mater. 2023 Jul 5:453:131354. doi: 10.1016/j.jhazmat.2023.131354.
Jianping Tang 1,  Fuli Zheng 2,  Xu Liu 1,  Yanjun Li 1,  Zhenkun Guo 1,  Xinpei Lin 1,  Jinfu Zhou 1,  Yu Zhang 1,  Guangxia Yu 2,  Hong Hu 2,  Wenya Shao 2,  Siying Wu 3,  Huangyuan Li 4
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou 350122, China.
  • 2 Fujian Provincial Key Laboratory of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou 350122, China; The Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou 350122, China.
  • 3 Fujian Provincial Key Laboratory of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, China; The Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou 350122, China. Electronic address: [email protected].
  • 4 Fujian Provincial Key Laboratory of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou 350122, China; The Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou 350122, China. Electronic address: [email protected].
PMID: 37054644 DOI: 10.1016/j.jhazmat.2023.131354
Abstract

Cobalt is the most widely used heavy metal pollutant in medicine and industry. Excessive cobalt exposure can adversely affect human health. Neurodegenerative symptoms have been observed in cobalt-exposed populations; however, the underlying mechanisms remain largely unknown. In this study, we demonstrate that the N6-methyladenosine (m6A) demethylase fat mass and obesity-associated gene (FTO) mediates cobalt-induced neurodegeneration by impairing autophagic flux. Cobalt-induced neurodegeneration was exacerbated through FTO genetic knockdown or repression of demethylase activity, but was alleviated by FTO overexpression. Mechanistically, we showed that FTO regulates TSC1/2-mTOR signaling pathway by targeting TSC1 mRNA stability in an m6A-YTHDF2 manner, which resulted in autophagosome accumulation. Furthermore, FTO decreases lysosome-associated membrane protein-2 (LAMP2) to inhibit the integration of autophagosomes and lysosomes, leading to autophagic flux damage. In vivo experiments further identified that central nervous system (CNS)-Fto-specific knockout resulted in serious neurobehavioral and pathological damage as well as TSC1-related Autophagy impairment in cobalt-exposed mice. Interestingly, FTO-regulated Autophagy impairment has been confirmed in patients with hip replacement. Collectively, our results provide novel insights into m6A-modulated Autophagy through FTO-YTHDF2 targeted TSC1 mRNA stability, revealing cobalt is a novel epigenetic hazard that induces neurodegeneration. These findings suggest the potential therapeutic targets for hip replacement in patients with neurodegenerative damage.

Keywords

Autophagic flux; Cobalt chloride; Epigenetic hazard; MRNA stability; Neurodegenerative damage.

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