The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults

Levi J. Yant, Qitao Ran, Lin Rao, Holly Van Remmen, Toru Shibatani, Jason G. Belter, Lucia Motta, Arlan Richardson, Tomas A. Prolla

Research output: Contribution to journalArticle

412 Scopus citations

Abstract

Lipid peroxidation has been implicated in a variety of pathophysiological processes, including inflammation, atherogenesis, neurodegeneration, and the ageing process. Phospholipid hydroperoxide glutathione peroxidase (GPX4) is the only major antioxidant enzyme known to directly reduce phospholipid hydroperoxides within membranes and lipoproteins, acting in conjunction with alpha tocopherol (vitamin E) to inhibit lipid peroxidation. Here we describe the generation and characterization of GPX4-deficient mice by targeted disruption of the murine Gpx4 locus through homologous recombination in embryonic stem cells. Gpx4-/- embryos die in utero by midgestation (E7.5) and are associated with a lack of normal structural compartmentalization. Gpx4+/- mice display reduced levels of Gpx4 mRNA and protein in various tissues. Interestingly, cell lines derived from Gpx4+/- mice are markedly sensitive to inducers of oxidative stress, including γ-irradiation, paraquat, tert-butylhydroperoxide, and hydrogen peroxide, as compared to cell lines derived from wild-type control littermates. Gpx4+/- mice also display reduced survival in response to gamma-irradiation. Our observations establish GPX4 as an essential antioxidant enzyme in mice and suggest that it performs broad functions as a component of the mammalian antioxidant network.

Original languageEnglish (US)
Pages (from-to)496-502
Number of pages7
JournalFree Radical Biology and Medicine
Volume34
Issue number4
DOIs
StatePublished - Feb 15 2003

Keywords

  • Free radicals
  • Glutathione Peroxidase
  • Reactive oxygen species
  • γ-Irradiation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Fingerprint Dive into the research topics of 'The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults'. Together they form a unique fingerprint.

  • Cite this

    Yant, L. J., Ran, Q., Rao, L., Van Remmen, H., Shibatani, T., Belter, J. G., Motta, L., Richardson, A., & Prolla, T. A. (2003). The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radical Biology and Medicine, 34(4), 496-502. https://doi.org/10.1016/S0891-5849(02)01360-6