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
  • 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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