Mitochondrial oxidative stress in mice lacking the glutathione peroxidase-1 gene.
Oxidative stress resulting from mitochondrially derived reactive oxygen species (ROS) has been hypothesized to damage mitochondrial oxidative phosphorylation (OXPHOS) and to be a factor in aging and degenerative disease. If this hypothesis is correct, then genetically inactivating potential mitochondrial antioxidant enzymes such as glutathione peroxidase-1 (Gpx1; EC 1.11.1.9) should increase mitochondrial ROS production and decrease OXPHOS function. To determine the expression pattern of Gpx1, isoform-specific antibodies were generated and mutant mice were prepared in which the Gpx1 protein was substituted for by beta-galactosidase, driven by the Gpx1 promoter. These experiments revealed that Gpx1 is highly expressed in both the mitochondria and the cytosol of the liver and kidney, but poorly expressed in heart and muscle. To determine the physiological importance of Gpx1, mice lacking Gpx1 were generated by targeted mutagenesis in mouse ES cells. Homozygous mutant Gpx1(tm1Mgr) mice have 20% less body weight than normal animals and increased levels of lipid peroxides in the liver. Moreover, the liver mitochondria were found to release markedly increased hydrogen peroxide, a Gpx1 substrate, and have decreased mitochondrial respiratory control ratio and power output index. Hence, genetic inactivation of Gpx1 resulted in growth retardation, presumably due in part to reduced mitochondrial energy production as a product of increased oxidative stress.
Esposito
L A
LA
Center for Molecular Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kokoszka
J E
JE
Waymire
K G
KG
Cottrell
B
B
MacGregor
G R
GR
Wallace
D C
DC
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000235:genetics; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption; D011247:Pregnancy; D000094765:Glutathione Peroxidase GPX1
D017931:DNA Primers; D005609:Free Radicals; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse