Impaired mitochondrial biogenesis in hippocampi of rats with chronic seizures.

Mitochondrial dysfunction has been suggested to be a contributing factor of epilepsy, but the underlying mechanisms are not completely explored. Mitochondrial biogenesis is involved in regulation of mitochondrial content, morphology, and function. In the current study, we show mitochondrial biogenesis severely impaired in hippocampi of rats with chronic seizures induced by pilocarpine, as evidenced by decreased mitochondrial DNA (mtDNA) content and decreased mtDNA-encoded protein level. Furthermore, we show mtDNA transcription and replication reduced in rats with chronic seizures. These defects were independent of downregulation of mitochondrial biogenesis-related factors, such as peroxisome proliferator-activated receptor gamma coactivator-1α, nuclear respiratory factor-1, and mitochondrial transcription factor A (Tfam), but depended on reduced Tfam–DNA binding activity. The present study suggests novel mechanisms for mitochondrial dysfunction during chronic seizures.