Oxidative Damage and the Mitochondrial Membrane in Age-related Cataract





N.S. Wolf, W.R. Pendergrass, P.E. Penn, G.M. Martin, H. VanRemmen

Department of Pathology, Box 357470, University of Washington, Seattle, WA 98195-7470, USA



Age-related cataract in humans and lower animals is widely held to be caused by or influenced by oxidative damage. We have documented the development of age-related cataract in several normal (non-mutant) strains of mice and rats. It is strongly susceptible to alterations in the normal levels of anti-oxidant enzymes present in the lens and, especially, in the mitochondria of the lens epithelial cells. Mitochondrial membrane potential (a result of proton gradient between outside and inside the inner membrane), and the presemce of peroxides can be measured in living ex vivo lenses by means of specific fluorescent dyes. Using this method we determined a decrease in mitochondrial membrane potential and an increase in peroxide presence in the lenses of old mice with advanced lens opacities, versus those of young animals. In mice with knockout of the gene for glutathione peroxidase-1 (normally present in the lens and active in breakdown of H202), the incidence and severity of cataracts were significantly increased. In mice transgenic for human catalase directed to the mitochondria (but not in controls in which this enzyme is directed to the nucleus or peroxisome) the incidence and severity of cataracts were significantly decreased and, coincidentally, mean life span was also extended. Our findings suggest 1) a role for oxidative free radicals and peroxides of mitochondrial origin in the development of age-related cataract, 2) an age-related loss of mitochondrial efficiency resulting in an increase in peroxides released, 3) accompanied by a decreased efficiency of peroxide breakdown by key mitochondrial anti-oxidant enzymes. In addition, the rate of development of age-related cataract may represent a biomarker for multisystem oxidative damages that affect animal life span.




Key words: mitochondria, oxidative damage, lens, anti-oxidant genes







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