Journal
GERIATRICS & GERONTOLOGY INTERNATIONAL
Volume 10, Issue -, Pages S70-S79Publisher
WILEY
DOI: 10.1111/j.1447-0594.2010.00604.x
Keywords
conditional knockout mice; manganese superoxide dismutase; mitochondria; oxidative stress; superoxide
Categories
Funding
- Program for Promotion of Basic Research Activities for Innovative Bioscience
- Ministry of Education, Science, Culture, Sports, and Technology
- Ministry of Health, Labour, and Welfare
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Manganese superoxide dismutase (Mn-SOD) is a mitochondrial enzyme that converts toxic O-2- to H2O2. Previous studies have reported that a systemic deficiency in Mn-SOD causes neonatal lethality in mice. Therefore, no mouse model is available for the analysis of the pathological role of O-2- injuries in adult tissues. To explore an adult-type mouse model, we generated tissue-specific Mn-SOD conditional knockout mice using a Cre-loxp system. First, we generated liver-specific Mn-SOD-deficient mice by crossbreeding with albumin-Cre transgenic mice. Mn-SOD proteins were significantly downregulated in the liver of liver-specific Mn-SOD knockout mice. Interestingly, the mutant mice showed no obvious morphological abnormalities or biochemical alterations in the liver, suggesting a redundant or less important physiological role for Mn-SOD in the liver than previously thought. Next, we generated heart/muscle-specific Mn-SOD-deficient mice by crossbreeding muscle creatine kinase-Cre transgenic mice. The mutant mice developed progressive dilated cardiomyopathy with specific molecular defects in mitochondrial respiration. Furthermore, brain-specific Mn-SOD-deficient mice that had been developed by crossbreeding with nestin-Cre transgenic mice developed a spongiform encephalopathy-like pathology associated with gliosis and died within 3 weeks of birth. These results imply that the superoxide generated in mitochondria plays a pivotal role in the development and progression of pathologies in the heart and brain, but not in the liver. In conclusion, we successfully generated various tissue-specific Mn-SOD conditional knockout mice that provide useful tools for the analysis of various oxidative stress-associated diseases. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S70-S79.
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