Interrogating the in vivo significance of selenium-based catlysis of GPX4 for mammalian development and survival

Glutathione peroxidase 4 (Gpx4) is a selenoprotein in mammals but Cys-containing homolog are found in other organisms. Its unique ability to reduce phospholipid hydroperoxides was reported to be necessary to suppress ferroptosis. To investigate the evolutionary advantage of selenolate- vs. thiolate-based catalysis in Gpx4, a transgenic mouse line was generated where the critical Sec of Gpx4 was replaced by Cys. Using this mouse line it was possible to show that the Cys variant of Gpx4 is sufficient for the survival of adult animals but Sec in Gpx4 is essential for embryogenesis and neurodevelopment in mice due to its inherent resistance towards peroxide-induced overoxidation.