Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Selenoproteins, rare proteins containing the 21st amino acid selenocysteine, differ from cysteine by selenium substitution.
• The catalytic advantage of selenolate over thiolate remains unclear, as many selenoproteins have cysteine homologs.

Purpose of the Study:

• To investigate the specific role of selenocysteine-containing GPX4 in mammalian development and neurological function.
• To elucidate the mechanistic basis for GPX4's catalytic activity and its implications for cell survival.

Main Methods:

• Utilized genetic manipulation to create cysteine variants of GPX4 in mice.
• Assessed developmental phenotypes, focusing on embryogenesis and interneuron survival.
• Investigated cellular responses to oxidative stress, including ferroptosis induction.
• Examined the impact of deleting other selenoproteins in the presence of GPX4 variants.

Main Results:

• Selenocysteine-based catalysis in GPX4 is dispensable for normal embryogenesis but essential for interneuron survival, preventing epilepsy.
• GPX4's selenocysteine moiety confers resistance to overoxidation, protecting cells from peroxide-induced ferroptosis.
• Cells with GPX4 cysteine variants are highly sensitive to peroxide-induced ferroptosis.
• Selenoproteins are dispensable for cell viability if partial GPX4 activity is maintained.

Conclusions:

• This study identifies a specific, indispensable role for selenium via GPX4 in preventing fatal epileptic seizures.
• GPX4's unique catalytic properties conferred by selenocysteine are crucial for neuronal survival under oxidative stress.
• The findings provide a definitive function for selenium in mammals, 200 years after its discovery.