Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in Alzheimer's disease.
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.
Yoo
Min-Hyuk
MH
Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Gu
Xinglong
X
Xu
Xue-Ming
XM
Kim
Jin-Young
JY
Carlson
Bradley A
BA
Patterson
Andrew D
AD
Cai
Huaibin
H
Gladyshev
Vadim N
VN
Hatfield
Dolph L
DL
D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D018384:Oxidative Stress; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism
D000447:Aldehydes; D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D008054:Lipid Peroxides; D017382:Reactive Oxygen Species; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C027576:4-hydroxy-2-nonenal