Mitochondrial dysfunction in epilepsy

Abstract

Mitochondrial dysfunction has been identified as one potential cause of epileptic seizures. Impaired mitochondrial function has been reported for the seizure focus of patients with temporal lobe epilepsy and Ammon's horn sclerosis and of adult and immature animal models of epilepsy. Since mitochondrial oxidative phosphorylation provides the major source of ATP in neurons and mitochondria participate in cellular Ca²⁺ homeostasis and generation of reactive oxygen species, their dysfunction strongly affects neuronal excitability and synaptic transmission. Therefore, mitochondrial dysfunction is proposed to be highly relevant for seizure generation. Additionally, mitochondrial dysfunction is known to trigger neuronal cell death, which is a prominent feature of therapy-resistant epilepsy. For this reason mitochondria have to be considered as promising targets for neuroprotective strategies in epilepsy.

Introduction

Epilepsy is a frequent neurological disorder affecting about 0.5 to 0.7% of the population worldwide. The typical feature of epilepsy is recurrent seizures, which on a cellular level consist of synchronized discharges of large groups of neurons that interrupt normal brain function. Potential causes of epilepsy include gene mutations, inflammation as well as malformations, tumors and trauma of the brain leading to alterations of neurotransmitter receptors and ion channels, neuronal network reorganization, nitric oxide production and opening of the blood–brain barrier. Additionally, it is well known that epileptic seizures can occur as a presenting sign of mitochondrial dysfunction in the central nervous system. This is due to the fact that mitochondria generate the ATP that is essential for the excitability and survival of neurons. Neuronal mitochondria are highly dynamic organelles that divide, fuse, and move along axons and dendrites (Hollenbeck and Saxton, 2005). Their functions in neurons include the regulation of Ca²⁺, redox signaling, developmental and synaptic plasticity, and the determination of cell survival and death (Mattson et al., 2008). The importance of mitochondria for neurons is evident from the phenotypes of epilepsies caused by mutations in genes affecting oxidative phosphorylation. Generalized seizures have been observed in several forms of epilepsy, being associated with mutations in the mitochondrial DNA polymerase γ (POLG1) (Naviaux and Nguyen, 2004, Zsurka et al., 2008), mitochondrial tRNA^Lys (MT-TK) (Shoffner et al., 1990, Zeviani et al., 1993) and tRNA^Phe (MT-TF) (Zsurka et al., 2010) genes. More recently, evidence for a more general involvement of mitochondria also in sporadic forms of epilepsy has been accumulated (Kann et al., 2005, Kunz, 2002, Kunz et al., 2000). This might be related to the fact that mitochondria are intimately involved in pathways leading to neuronal cell death (Blümcke et al., 1999, Ott et al., 2007) seen in experimental and human epilepsy. Accumulating evidence indicates that free radicals, oxidative stress and mitochondrial dysfunction are important factors in the general pathogenesis of epilepsy (Jarrett et al., 2008a, Kann and Kovács, 2007, Kudin et al., 2009, Lin and Beal, 2006, Meldrum, 2002, Patel, 2004, Waldbaum and Patel, 2010). Therefore, it is reasonable to assume a considerable pathogenic role of mitochondrial dysfunction in the process of epileptogenesis and seizure generation.