Decrease of an intracellular organic osmolyte contributes to the cytotoxicity of organophosphate in neuroblastoma
Pan Wang1, Yi-Jun Wu2, Man-Lian Sun2
1Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 1-5 Beichenxilu Road, Beijing, 100101, China; School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
Abstract:
Organophosphorus compounds (OP) causes prominent delayed neuropathy in vivo and cytotoxicity to neuronal cells in vitro. The primary target protein of OP's neurotoxicity is neuropathy target esterase (NTE), which can convert phosphatidylcholine (PC) to glycerophosphocholine (GPC). Recent studies reveal that autophagic cell death is important for the initiation and progression of OP-induced neurotoxicity both in vivo and in vitro. However, the mechanism of how OP induces autophagic cell death is unknown. Here it is found that GPC is an important organic osmolyte in the neuroblastoma cells, and treatment with tri-o-cresyl phosphate (TOCP), a representative OP, leads to the decrease of GPC and imbalance of extracellular and intracellular osmolality. Knockdown of GPC metabolizing enzyme glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) reverses TOCP-induced autophagic cell death, which further supports the notion that the reduced GPC level leads to the autophagic cell death. Furthermore, it is found that autophagic cell death is due to the induction of reactive oxygen species (ROS) and mitochondrial damage by imbalance of osmolality with TOCP treatment. In summary, this study reveals that TOCP treatment decreases GPC level and intracellular osmolality, which induces ROS and mitochondrial damage and leads to the cell death and neurite degradation by autophagy. This study lays the foundation for further investigations on the potential therapeutic approaches for OP neurotoxicity or NTE mutation-related neurological diseases.
Insights
Organophosphorus compounds decrease glycerophosphocholine (GPC), an osmolyte, leading to cell death via autophagy. Restoring GPC levels prevents this neurotoxic effect, offering therapeutic insights.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Organophosphorus (OP) compounds cause neurotoxicity and delayed neuropathy.
- Autophagic cell death is implicated in OP-induced neurotoxicity, but the mechanism remains unclear.
- Neuropathy target esterase (NTE) is a key protein in OP neurotoxicity, metabolizing phosphatidylcholine (PC) to glycerophosphocholine (GPC).
Purpose of the Study:
- To elucidate the mechanism by which OP compounds induce autophagic cell death.
- To investigate the role of glycerophosphocholine (GPC) in OP-induced neurotoxicity.
- To explore potential therapeutic targets for OP neurotoxicity.
Main Methods:
- Treatment of neuroblastoma cells with tri-o-cresyl phosphate (TOCP), a representative OP.
- Measurement of GPC levels and assessment of intracellular/extracellular osmolality.
- Knockdown of glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5), an enzyme involved in GPC metabolism.
- Analysis of reactive oxygen species (ROS) production and mitochondrial damage.
Main Results:
- TOCP treatment reduced GPC levels and disrupted cellular osmolality.
- Knockdown of GDPD5 reversed TOCP-induced autophagic cell death, confirming the role of reduced GPC.
- Imbalance in osmolality induced ROS and mitochondrial damage, leading to autophagic cell death and neurite degradation.
Conclusions:
- OP-induced neurotoxicity, exemplified by TOCP, involves decreased GPC and subsequent osmolality imbalance.
- This osmolality disruption triggers ROS production and mitochondrial damage, culminating in autophagic cell death.
- Understanding this pathway provides a basis for developing therapies for OP neurotoxicity and related neurological disorders.
