Mitochondrial dysfunction and increased sensitivity to excitotoxicity in mice deficient in DNA mismatch repair
Simona Francisconi1, Mara Codenotti, Giulia Ferrari Toninelli
1Department of Biomedical Sciences and Biotechnologies, Centre of Excellence for Diagnostic and Therapeutic Innovations, University of Brescia, Brescia, Italy.
Abstract:
The expression profile in the hippocampus of mice lacking one allele of the MutS homologue (Msh2), gene, which is one of the most representative components of the DNA mismatch repair system, was analysed to understand whether defects in the repair or in response to DNA damage could impact significantly on brain function. The overall results suggested a reduction in mitochondrial function as indicated by gene expression analysis, biochemical and behavioural studies. In the hippocampus of Msh2+/- mice, array data, validated by RT-PCR and western blot analysis, showed reduced expression levels of genes for cytochrome c oxidase subunit 2 (CoxII), ATP synthase subunit beta and superoxide dismutase 1. Biochemically, mitochondria from the hippocampus and cortex of these mice show reduced CoxII and increased aconitase activity. Behaviourally, these alterations resulted in mice with increased vulnerability to kainic acid-induced epileptic seizures and hippocampal neuronal loss. These data suggest that lack of an efficient system involved in recognizing and repairing DNA damage may generate a brain mitochondriopathy.
Insights
Defects in DNA mismatch repair (Msh2) in mice led to reduced mitochondrial function in the brain. This brain mitochondriopathy increased seizure vulnerability and neuronal loss.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- DNA mismatch repair is crucial for genomic stability.
- Defects in DNA repair systems can impact cellular function.
- The role of DNA repair in brain function is not fully understood.
Purpose of the Study:
- To investigate the impact of DNA mismatch repair deficiency on brain function.
- To determine if Msh2 gene defects affect mitochondrial function in the brain.
- To explore the consequences of impaired DNA repair on neuronal health and behavior.
Main Methods:
- Gene expression analysis (microarrays, RT-PCR) in Msh2+/- mice hippocampus.
- Biochemical assays of mitochondrial enzyme activity (cytochrome c oxidase, aconitase).
- Behavioral studies assessing seizure susceptibility and neuronal loss.
Main Results:
- Reduced expression of mitochondrial genes (CoxII, ATP synthase, SOD1) in Msh2+/- mice.
- Biochemical evidence of mitochondrial dysfunction (decreased CoxII, increased aconitase activity).
- Mice exhibited increased vulnerability to kainic acid-induced seizures and hippocampal neuronal damage.
Conclusions:
- Impaired DNA mismatch repair system can lead to brain mitochondriopathy.
- Msh2 deficiency impacts mitochondrial function and neuronal integrity.
- DNA repair mechanisms are essential for maintaining brain health and function.
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