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(26) A MOUSE MODEL FOR MITOCHONDRIAL OXIDATIVE STRESS S. Melov
During the course of normal respiration, superoxide is produced which is normally scavenged by the mitochondrial form of superoxide dismutase (SOD2). The potential toxicity of this endogenously produced free radical can be seen through studies on mice which have had SOD2 inactivated through knockout technology. Mice that are homozygous null for sod2 die within the first week of life primarily of heart failure in association with a number of mitochondrial enzymatic abnormalities. We have been able to successfully extend the lifespan of these mice up to 5 fold, with concomitant attenuation of mitochondrial defects through treatment with synthetic SODs (SOD mimetics). Through variation of the properties of the SOD mimetic being used, we have been able to uncover many mitochondrial free radical mediated phenotypes in these mice, including seizures, a spongiform encephalopathy, and ataxia. We have directly observed regional neuronal cell death in the brains of these mice through specialized histological stains. This cell death can be attenuated in a dose dependent fashion through treatment with SOD mimetics. This implies that mitochondrial dysfunction caused by endogenous free radical production can be successfully treated with "mito-protective" compounds.
For further information contact...Carmen Mannella: carmen@wadsworth.org |
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