Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in alzheimer's disease

Min Hyuk Yoo, Xinglong Gu, Xue Ming Xu, Jin Young Kim, Bradley A. Carlson, Andrew D. Patterson, Huaibin Cai, Vadim N. Gladyshev, Dolph L. Hatfield

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Numerous studies characterizing the function of glutathione peroxidase 4 (GPx4) have demonstrated that this selenoenzyme is protective against oxidative stress. Herein, we characterized the function of this protein by targeting GPx4 downregulation using RNA interference. Partial knockdown of GPx4 levels resulted in growth retardation and morphological changes. Surprisingly, GPx4 knockdown cells showed virtually unchanged levels of intracellular ROS, yet highly increased levels of oxidized lipid by-products. GPx1, another glutathione peroxidase and a major cellular peroxide scavenging enzyme, did not rescue GPx4-deficient cells and did not reduce lipid peroxide levels. The data established an essential role of GPx4 in protecting cells against lipid hydroperoxide damage, yet a limited role as a general antioxidant enzyme. As oxidized lipid hydroperoxides are a characteristic of neurodegenerative diseases, we analyzed brain tissues of mice suffering from a model of Alzheimer's disease and found that oxidized lipid by-products were enriched, and expression of both GPx4 and guanine-rich sequence-binding factor, which is known to control GPx4 synthesis, was downregulated. Brain tissue from an Alzheimer's diseased human also manifested enhanced levels of one of the oxidized lipid by-products, 4-hydroxynonenal. These data suggest a role of GPx4 in neurodegenerative diseases through its function in removal of lipid hydroperoxides.

    Original languageEnglish (US)
    Pages (from-to)819-827
    Number of pages9
    JournalAntioxidants and Redox Signaling
    Volume12
    Issue number7
    DOIs
    StatePublished - Apr 1 2010

    ASJC Scopus subject areas

    • Biochemistry
    • Physiology
    • Molecular Biology
    • Clinical Biochemistry
    • Cell Biology

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