Review Mitochondrial involvement in temporal lobe epilepsy Alexei P. Kudin, Gábor Zsurka, Christian E. Elger, Wolfram S. Kunz ⁎ Division of Neurochemistry, Department of Epileptology, University Bonn Medical Center, Sigmund-Freud-Str. 25, D53105 Bonn, Germany abstract article info Article history: Received 1 December 2008 Revised 13 February 2009 Accepted 19 February 2009 Available online 5 March 2009 Keywords: Temporal lobe epilepsy Mitochondria Mitochondrial diseases Mitochondrial dysfunction has been identified as a potential cause of epileptic seizures and therapy-resistant forms of severe epilepsy. Thus, a broad variety of mutation in mitochondrial DNA or nuclear genes leading to the impairment of mitochondrial respiratory chain or of mitochondrial ATP synthesis has been associated with epileptic phenotypes. Additionally, with a variety of different methods impaired mitochondrial function has been reported for the seizure focus of patients with temporal lobe epilepsy and Ammon's horn sclerosis and of animal models of temporal lobe epilepsy. Since mitochondrial oxidative phosphorylation provides the major source of ATP in neurons and mitochondria participate in cellular Ca 2+ homeostasis, their dysfunction strongly affects neuronal excitability and synaptic transmission, which 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 temporal lobe epilepsy. Therefore, mitochondria have to be considered as promising targets for neuroprotective strategies in epilepsy. © 2009 Elsevier Inc. All rights reserved. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 Mitochondrial dysfunction is associated with inherited forms of epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 Mitochondrial dysfunction in human temporal lobe epilepsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328 Mitochondrial involvement in experimental epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 Mechanism of mitochondrial dysfunction caused hyperexcitability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 Brain energy metabolism as potential target of neuroprotective strategies in epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 Introduction Epilepsy is one of the most common neurological disorders affecting about 0.5 to 0.7% of the population worldwide. The hallmark of epilepsy is recurrent seizures, which on a cellular level is charac- terised by synchronized discharges of large groups of neurons that interrupt normal function. It is well known that epileptic seizures can occur as a presenting sign of mitochondrial dysfunction in the central nervous system. Generalised seizures have been observed in several forms of myoclonus epilepsy, being associated with mutations in the mitochondrial DNA polymerase γ (POLG) (Naviaux and Nguyen, 2004; Zsurka et al., 2008) or mitochondrial tRNA Lys genes (Shoffner et al., 1990; Zeviani et al., 1993). Partial seizures are frequently noticed in mitochondrial encephalopathies, including the MELAS syndrome, associated with mutations in the mitochondrial tRNA LeuUUR gene (Goto et al., 1990, 1991). More recently, evidence for a more general involvement of mitochondria also in sporadic forms of epilepsy has been accumulating (Kann et al., 2005; Kunz, 2002; Kunz et al., 2000). From one hand side, this is related to the fact that mitochondria are intimately involved in pathways leading to neuronal cell death (Krajewski et al., 1999) seen in both experimental and human epi- lepsy. In addition, there is a growing body of evidence that mito- chondrial dysfunction plays a considerable role in the process of epileptogenesis and seizure generation in temporal lobe epilepsy with Ammon's horn sclerosis — a subclass of therapy-resistant forms of epilepsy. Mitochondrial dysfunction is associated with inherited forms of epilepsy Defects of oxidative phosphorylation in the CNS are the characte- ristic sign of mitochondrial encephalopathies. In a broad variety of Experimental Neurology 218 (2009) 326–332 ⁎ Corresponding author. Fax: +49 228 6885 290. E-mail address: wolfram.kunz@ukb.uni-bonn.de (W.S. Kunz). 0014-4886/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2009.02.014 Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr