Methylmercury induces ferroptosis by suppressing GPX4 protein levels in C17.2 mouse neural stem cells

Area of Science:

• Neuroscience
• Toxicology
• Cell Biology

Background:

• Minamata disease results from methylmercury toxicity, primarily affecting the central nervous system.
• The precise mechanisms of methylmercury neurotoxicity, particularly its role in programmed cell death, are not fully understood.
• Ferroptosis, an iron-dependent form of cell death involving lipid peroxidation, is a potential pathway for methylmercury-induced neuronal damage.

Purpose of the Study:

• To investigate the role of ferroptosis in methylmercury-induced neuronal cell death.
• To elucidate the molecular mechanisms by which methylmercury triggers ferroptosis in neural stem cells.

Main Methods:

• Utilized C17.2 mouse neural stem cells to study methylmercury toxicity.
• Administered ferroptosis inhibitors (ferrostatin-1, liproxstatin-1, deferoxamine) to assess their protective effects.
• Measured intracellular reactive oxygen species, lipid peroxides, cystine transporter (xCT/SLC7A11), and glutathione peroxidase 4 (GPX4) levels.
• Examined the impact of GPX4 overexpression on methylmercury resistance.

Main Results:

• Ferroptosis inhibitors significantly reduced methylmercury-induced cell death.
• Methylmercury exposure increased reactive oxygen species and lipid peroxides.
• xCT mRNA and protein levels increased, while GPX4 protein levels decreased following methylmercury exposure.
• Overexpression of GPX4 conferred resistance to methylmercury toxicity.

Conclusions:

• Methylmercury induces ferroptosis in neural stem cells.
• The mechanism involves the suppression of GPX4 protein levels, leading to increased lipid peroxidation and cell death.
• These findings clarify a key pathway in methylmercury neurotoxicity.