Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain

Glutathione peroxidase 4 (Gpx4) is an antioxidant defense enzyme important in reducing hydroperoxides in membrane lipids and lipoproteins. Gpx4 is essential for survival of embryos and neonatal mice; however, whether Gpx4 is required for adult animals remains unclear. In this study, we generated a floxed Gpx4 mouse (Gpx4(f/f)), in which exons 2–4 of Gpx4 gene are flanked by loxP sites. We then cross-bred the Gpx4(f/f) mice with a tamoxifen (tam)-inducible Cre transgenic mouse (R26CreER mice) to obtain mice in which the Gpx4 gene could be ablated by tam administration (Gpx4(f/f)/Cre mice). After treatment with tam, adult Gpx4(f/f)/Cre mice (6–9months of age) showed a significant reduction of Gpx4 levels (a 75–85% decrease) in tissues such as brain, liver, lung, and kidney. Tam-treated Gpx4(f/f)/Cre mice lost body weight and died within 2weeks, indicating that Gpx4 is essential for survival of adult animals. Tam-treated Gpx4(f/f)/Cre mice exhibited increased mitochondrial damage, as evidenced by the elevated 4-hydroxylnonenal (4-HNE) level, decreased activities of electron transport chain complexes I and IV, and reduced ATP production in liver. Tam treatment also significantly elevated apoptosis in Gpx4(f/f)/Cre mice. Moreover, tam-treated Gpx4(f/f)/Cre mice showed neuronal loss in the hippocampus region and had increased astrogliosis. These data indicate that Gpx4 is essential for mitochondria integrity and survival of neurons in adult animals. A conditional knockout mouse model, in which Gpx4 gene can be ablated by the administration of tamoxifen, was generated. Tamoxifen treatment of adult conditional knockout mice resulted in death that was directly correlated with elevated mitochondrial damage, indicating that Gpx4 is essential for the survival of adult animals. [Display omitted] ► A conditional Gpx4 knockout mouse model was generated. ► Gpx4 ablation in adult mice was lethal. ► Adult Gpx4 knockout mice showed elevated mitochondrial damage. ► Adult Gpx4 knockout mice had neurodegeneration in hippocampus.