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Manganese-induced miR-125b-2-3p promotes anxiety-like behavior via TFR1-mediated ferroptosis
Honggang Chen1, Jinxia Wu1, Xiaozheng Zhu1
1Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
Abstract:
The toxic effects of excessive manganese (Mn) levels in the environment have led to a severe public health concern. Ferroptosis is a newly form of cell death relying on iron, inherent to pathophysiological processes of psychiatric disorders, such as anxiety and depression-like behaviors. Excessive Mn exposure causes various neurological effects, including neuronal death and mood disorders. Whether Mn exposure causes anxiety and depression-like behaviors, and the underlying mechanisms of Mn-induced ferroptosis have yet to be determined. Here, Mn-exposed mice showed anxiety-like behavior. We also confirmed the accumulation of ferrous ion (Fe2+), lipid peroxidation, and depletion of antioxidant defense system both in vitro and in vivo Mn-exposed models, suggesting that Mn exposure can induce ferroptosis. Furthermore, Mn exposure downregulated the expression of miR-125b-2-3p. In turn, overexpression of miR-125b-2-3p alleviated the Mn-induced ferroptosis by targeting Transferrin receptor protein 1 (TFR1). In summary, this novel study established the propensity of Mn to cause anxiety-like behavior, an effect that was regulated by miR-125b-2-3p and ensuing ferroptosis secondary to the targeting of TFR1. These results offer promising targets for the prevention and treatment of Mn-induced neurotoxicity.
Insights
Excessive manganese (Mn) exposure induces anxiety-like behaviors and ferroptosis, a form of cell death. This neurotoxicity is linked to miR-125b-2-3p downregulation and iron accumulation, offering potential therapeutic targets.
Area of Science:
- Neuroscience
- Environmental Health
- Cell Biology
Background:
- Excessive manganese (Mn) exposure is a public health concern linked to neurological effects and mood disorders.
- Ferroptosis, an iron-dependent cell death, is implicated in psychiatric disorders like anxiety and depression.
Purpose of the Study:
- To investigate if Mn exposure induces anxiety- and depression-like behaviors.
- To elucidate the underlying mechanisms of Mn-induced ferroptosis.
Main Methods:
- Mn-exposed mouse models (in vitro and in vivo) were used to assess behavioral changes.
- Ferrous ion accumulation, lipid peroxidation, and antioxidant system status were analyzed.
- Expression levels of miR-125b-2-3p and its target, Transferrin receptor protein 1 (TFR1), were examined.
Main Results:
- Mn exposure in mice resulted in anxiety-like behavior.
- Evidence of ferroptosis, including Fe2+ accumulation, lipid peroxidation, and depleted antioxidants, was observed.
- Mn exposure downregulated miR-125b-2-3p, while its overexpression protected against Mn-induced ferroptosis by targeting TFR1.
Conclusions:
- Mn exposure can induce anxiety-like behavior and ferroptosis.
- The miR-125b-2-3p/TFR1 pathway is a key regulator of Mn-induced ferroptosis and neurotoxicity.
- Targeting this pathway may offer novel strategies for preventing and treating Mn neurotoxicity.
