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PMID:14980699

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Citation

Liang, LP and Patel, M (2004) Mitochondrial oxidative stress and increased seizure susceptibility in Sod2(-/+) mice. Free Radic. Biol. Med. 36:542-54

Abstract

Epileptic seizures can occur as a result of mitochondrial dysfunction. Mitochondria have vital functions such as energy generation, control of cell death, neurotransmitter synthesis, and free radical production. Which of these critical mitochondrial functions contributes to epileptic seizures is unknown. We demonstrate here that a subset of mice with partial deficiency of the mitochondrial superoxide dismutase (Sod2(-/+)) show increased incidence of spontaneous and handling-induced seizures that correlates with chronic mitochondrial oxidative stress (increased aconitase inactivation and 8-hydroxy-2'-deoxyguanosine formation in mitochondria) and diminished mitochondrial oxygen utilization. Before the age at which spontaneous seizures appear in a subset of the mice, Sod2(-/+) mice demonstrated increased susceptibility to behavioral seizures, mitochondrial aconitase inactivation, and neurodegeneration induced by the administration of kainate. These data suggest that chronic mitochondrial oxidative stress initiated by superoxide (O(2)(.-)) radicals is sufficient to increase seizure susceptibility due to aging, environmental stimulation, or excitotoxin administration. Sod2(-/+) mice showed an age-related decrease in the expression of glial glutamate transporters (GLT-1 and GLAST), suggesting that oxidant-induced inhibition of glutamate transport may play a mechanistic role in rendering some Sod2(-/+) mice susceptible to seizures. In summary, mitochondrial oxidative stress and resultant dysfunction may be an important mechanism underlying certain seizure disorders.

Links

PubMed Online version:10.1016/j.freeradbiomed.2003.11.029

Keywords

Aconitate Hydratase/metabolism; Amino Acid Transport System X-AG/metabolism; Animals; Deoxyadenosines/metabolism; Epilepsy/metabolism; Excitatory Amino Acid Transporter 2/metabolism; Glutamic Acid/metabolism; Kainic Acid/pharmacology; Mice; Mice, Knockout; Mitochondria/drug effects; Mitochondria/metabolism; Neurodegenerative Diseases/chemically induced; Neurodegenerative Diseases/metabolism; Neurotoxins/toxicity; Oxidative Stress; Oxygen/metabolism; Seizures/chemically induced; Seizures/metabolism; Superoxide Dismutase/genetics; Superoxide Dismutase/metabolism; Superoxides/toxicity

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SODM

involved_in

GO:0001315: age-dependent response to reactive oxygen species

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SODM

enables

GO:0004784: superoxide dismutase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SODM

involved_in

GO:0006801: superoxide metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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