Mitochondrial dysfunction and increased sensitivity to excitotoxicity in mice deficient in DNA mismatch repair.
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.
Francisconi
Simona
S
Department of Biomedical Sciences and Biotechnologies, Centre of Excellence for Diagnostic and Therapeutic Innovations, University of Brescia, Brescia, Italy.
Codenotti
Mara
M
Ferrari Toninelli
Giulia
G
Uberti
Daniela
D
Memo
Maurizio
M
D000818:Animals; D020137:Base Pair Mismatch / Q000502:physiology*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods; D007608:Kainic Acid / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis / Q000379:methods; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051718:MutS Homolog 2 Protein / Q000172:deficiency*; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D018690:Excitatory Amino Acid Agonists; D012333:RNA, Messenger; D003576:Electron Transport Complex IV; D051718:MutS Homolog 2 Protein; D007608:Kainic Acid