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Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury
Ye-Shih Ho1, Ye Xiong, Wanchao Ma
1Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, Michigan 48201, USA. yho@wayne.edu
Abstract:
Catalase plays a major role in cellular antioxidant defense by decomposing hydrogen peroxide, thereby preventing the generation of hydroxyl radical by the Fenton reaction. The degree of catalase deficiency in acatalasemic and hypocatalasemic mice varies from tissue to tissue. They therefore may not be suitable for studying the function of this enzyme in certain models of oxidant-mediated tissue injury. We sought to generate a new line of catalase null mice by the gene targeting technique. The mouse catalase (Cat or Cas1) gene was disrupted by replacing parts of intron 4 and exon 5 with a neomycin resistance cassette. Homozygous Cat knockout mice, which are completely deficient in catalase expression, develop normally and show no gross abnormalities. Slices of liver and lung and lenses from the knockout mice exhibited a retarded rate in decomposing extracellular hydrogen peroxide compared with those of wild-type mice. However, mice deficient in catalase were not more vulnerable to hyperoxia-induced lung injury; nor did their lenses show any increased susceptibility to oxidative stress generated by photochemical reaction, suggesting that the antioxidant function of catalase in these two models of oxidant injury is negligible. Further studies showed that cortical injury from physical impact caused a significant decrease in NAD-linked electron transfer activities and energy coupling capacities in brain mitochondria of Cat knockout mice but not wild-type mice. The observed decrease in efficiency of mitochondrial respiration may be a direct result of an increase in mitochondrion-associated calcium, which is secondary to the increased oxidative stress. These studies suggest that the role of catalase in antioxidant defense is dependent on the type of tissue and the model of oxidant-mediated tissue injury.
Insights
Catalase (Cat) knockout mice, completely deficient in the enzyme, develop normally. Their antioxidant role varies by tissue, with significant impact observed in brain mitochondria following injury.
Area of Science:
- Biochemistry
- Genetics
- Cellular Biology
Background:
- Catalase is crucial for cellular antioxidant defense by breaking down hydrogen peroxide.
- Existing catalase-deficient mouse models (acatalasemic, hypocatalasemic) exhibit variable enzyme deficiency across tissues, limiting their use in specific oxidant injury studies.
- A complete catalase deficiency model is needed to precisely investigate the enzyme's function.
Purpose of the Study:
- To generate and characterize a novel line of catalase null mice using gene targeting.
- To investigate the role of catalase in different tissues and oxidant-mediated injury models.
Main Methods:
- Gene targeting was employed to disrupt the mouse catalase (Cat or Cas1) gene, replacing key introns and exons with a neomycin resistance cassette.
- Homozygous Cat knockout mice were generated and assessed for gross abnormalities and catalase expression.
- Tissue samples (liver, lung, lens, brain mitochondria) from knockout and wild-type mice were used to evaluate hydrogen peroxide decomposition rates, susceptibility to hyperoxia-induced lung injury, photochemical oxidative stress in lenses, and mitochondrial function after physical cortical injury.
Main Results:
- Homozygous Cat knockout mice, completely deficient in catalase, developed normally without gross abnormalities.
- These mice showed reduced extracellular hydrogen peroxide decomposition in liver, lung, and lens tissues compared to wild-type.
- Contrary to expectations, catalase-deficient mice were not more vulnerable to hyperoxia-induced lung injury or photochemical lens damage.
- Physical cortical injury led to decreased mitochondrial NAD-linked electron transfer and energy coupling in Cat knockout mice, but not wild-type mice, suggesting increased oxidative stress and mitochondrion-associated calcium.
Conclusions:
- Catalase deficiency in mice does not universally impair antioxidant defense and its protective role is context-dependent.
- The enzyme's significance varies with tissue type and the specific model of oxidant-mediated injury.
- Catalase plays a critical role in protecting brain mitochondria from oxidative stress following physical trauma, potentially via calcium regulation.
