title: Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain.
abstract: 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 (6-9 months 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 2 weeks, 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.
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, TX 78229, USA.
authors.forename: Si-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Liuji
authors.initials: L
authors.lastname: Chen
authors.forename: Ren
authors.initials: R
authors.lastname: Na
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Carmen
authors.initials: C
authors.lastname: Rios
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
authors.forename: Qitao
authors.initials: Q
authors.lastname: Ran
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000201:enzymology*; D017931:DNA Primers; D005804:Genes, Lethal; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D010641:Phenotype; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D016133:Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000447:Aldehydes; D017931:DNA Primers; D013629:Tamoxifen; D000255:Adenosine Triphosphate; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C027576:4-hydroxy-2-nonenal