Cytochrome c oxidase deficit is associated with the seizure onset zone in young patients with focal cortical dysplasia Type II

Abstract

It has been postulated that mitochondrial dysfunction may be an important factor in epileptogenesis of intractable epilepsy. The current study tests the hypothesis that mitochondrial Complex IV (CIV) or cytochrome c oxidase dysfunction is associated with the seizure onset zone (SOZ) in patients with focal cortical dysplasia (FCD). Subjects were selected based on: age <19y; epilepsy surgery between May, 2010 and October, 2011; pathological diagnosis of isolated focal cortical dysplasia Type I (FCDI) or Type II (FCDII); and sufficient residual cortical tissue to conduct analysis of electron transport chain complex (ETC) activity in SOZ and adjacent cortical regions. In this retrospective study, patients were identified who had sufficient unfixed, frozen brain tissue for biochemical analysis in tissue homogenates. Specimens were subtyped using ILAE classification for FCD, and excluded if diagnosed with FCD Type III or dual pathology. Analysis of ETC activity in resected tissues was conducted independently and without knowledge of the identity, diagnosis, or clinical status of individual subjects. Seventeen patients met the inclusion criteria, including 6 FCDI and 11 FCDII. Comparison of adjacent cortical resections showed decreased CIV activity in the SOZ of the FCDII group (P = 0.003), but no significant CIV difference in adjacent tissues of the FCDI group. Because of the importance of CIV as the terminal and rate-limiting complex in the mitochondrial electron transport chain, these authors conclude that 1) a deficit of CIV is associated with the SOZ of patients with FCDII; 2) CIV deficiency may contribute to the spectrum of FCD neuropathology; and 3) further investigation of CIV in FCD may lead to the discovery of new targets for neuroprotective therapies for patients with intractable epilepsy.

Regional distribution of cytochrome c oxidase activity and copper in sclerotic hippocampi of epilepsy patients

“…Our results strongly imply that HS, CCO, and Cu are related, and substantiate previous findings that have related seizures and epileptogenesis with dysfunctional mitochondria and CCO deficiency and the loss of Cu homeostasis (Hallmann et al., 2016; Miles et al., 2015; Rezek & Moore, 1986; Yamamoto & Tang, 1996; Zsurka & Kunz, 2015). CCO showed decreased activity in regions with pyramidal neurons somata that were most affected by sclerosis—PY1 and CA4.…”

“…CCO contains three Cu ions in two centers (binuclear Cu A and mononuclear Cu B ), which are essential for passing electrons from complex III and cytochrome c to O 2 (Yoshikawa et al., 2011). CCO deficiency and inhibition have been related to the development of seizures and epileptic phenotype (Hallmann et al., 2016; Miles et al., 2015; Rezek & Moore, 1986; Yamamoto & Tang, 1996; Zsurka & Kunz, 2015). Finally, a decrease in CCO activity has been observed in seizure onset zones in focal cortical dysplasia (Miles et al., 2015).…”