Mitochondrial oxidative stress in mice lacking the glutathione peroxidase-1 gene

Oxidative stress resulting from mitochondrially derived reactive oxygen spe cies (ROS) has been hypothesized to damage mitochondrial oxidative phosphor ylation (OXPHOS) and to be a factor in aging and degenerative disease. if t his hypothesis is correct, then genetically inactivating potential mitochon drial antioxidant enzymes such as glutathione peroxidase-1 (Gpx1: EC 1.11.1 .9) should increase mitochondrial ROS production and decrease OXPHOS functi on. To determine the expression pattern of Gpx1, isoform-specific antibodie s were generated and mutant mice were prepared in which the Gpx I protein w as substituted for by beta-galactosidase, driven by the Gpx1 promoter. Thes e experiment!, revealed that Gpx1 is highly expressed in both the mitochond ria 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(tm/Mgr) mice have 20% less body weight than normal animals and increased levels of lipid peroxides in the liver. Moreover, the liver mitoc hondria were found to release markedly increased hydrogen peroxide, a Gpx1 substrate, and have decreased mitochondrial respiratory control ratio and p ower output index. Hence, genetic inactivation of Gpx1 resulted in growth r etardation, presumably due in part to reduced mitochondrial energy producti on as a product of increased oxidative stress. Copyright (C) 2000 Elsevier Science Inc.