Hannah R Cock

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Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London WC1N 3BG, UK

Abstract: Studies in vitro and in other disease states where excitotoxicity is believed to be important have demonstrated that mitochondrial function is a critical determinant of cell death, reflecting key roles in intracellular calcium homeostasis, energy production and oxidative stress. Central to this is the process of mitochondrial permeability transition, for which there are numerous influencing factors, although many, if not all, may specifically act though effects on the redox state of the cell and oxidative stress. Mitochondrial function in relation to seizure-induced cell death has been little studied until recently, but there is now accumulating evidence that similar mechanisms operate, certainly in cell death, following prolonged seizures. To what extent these same mechanisms might contribute to non-fatal but pathologically significant functional cellular changes in epilepsy, and the significance of reported free radical production after brief seizures is as yet uncertain. However, with the wide range of established techniques available to study mitochondrial function and oxidative stress, and those currently under development, these questions are undoubtedly answerable in the near future. Increased understanding of the mechanisms involved in seizure-induced cellular damage is an essential basis for the development of rational neuroprotective strategies.

Introduction

Seizure activity results in a large number of changes and cascades of events at a cellular level. Changes in gene expression, receptor composition, synaptic physiology and the activation of some late cell death pathways (e.g. caspase activation) will have been covered elsewhere. This chapter will focus on the potential role of mitochondria, including their capacity to produce free radicals, in seizure-associated neuronal damage. Following an introduction to normal mitochondrial functions, I will briefly discuss some of the methodological issues in this area. I will

* Correspondence to: H.R. Cock, Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London WC1N 3BG, UK. Tel.: +44-207-8373611, ext. 4256; Fax: +44-207-278-5616; E-mail: [email protected]

then summarize the major conclusions from studies on neuronal death in vitro and in other disease states, where there has been extensive work on excitotoxic cell death, which underpins the more limited work to date in epilepsy. Finally, I will review the work that has been done in this field with respect to seizure-associated cell death, before concluding with my own perspective on the future in this area.

Mitochondrial structure and function

Mitochondria are ubiquitous intracellular organelles, whose primary function is the production of cellular energy in the form of adenosine triphospate (ATP) from food-derived fuels. Each mitochondrion (Fig. 1) consists of a double membrane-bound structure, with an internal matrix in which many metabolic systems involved in breaking down food fuels reside. These include the fatty acid fJ-oxidation enzymes, and those of the tricarboxylic

O mtDNA

Iriner membrane outer membrane

Matrix fatty acids itine

Fig. 1. Schematic representation of a mitochondrion. See text for details. mtDNA, mitochondrial DNA; MPT, mitochondrial permeability transition; TCA, tricarboxylic acid cycle; I, II, III, IV, V, complexes of the mitochondrial respiratory chain.

acid (TCA/Kreb's) cycle to break down carbohydrates. Electrons from these systems are passed to the mitochondrial respiratory chain (MRC) situated on the inner mitochondrial membrane, which through a series of enzymatic processes (complexes I-IV), passes the electrons to the final acceptor, oxygen, which is reduced to water (Darley-Usmar et al., 1994). At complexes I, III and IV, electron transport is coupled to vectoral proton translocation, creating an electrochemical gradient across the inner mitochondrial membrane. This potential energy is then utilized by Complex V to generate ATR ATP is the basic unit of cellular energy and as such not only a pre-requisite for cell survival, but also essential for a wide range of cellular functions (McCormack and Denton, 1994), including several ionic homeostasis mechanisms (e.g. Na+-K+ ATPase; Na+-Ca2+ ATPase), repair systems, and the ability of neurons to generate action potentials.

In addition to their oxidative metabolism function, mitochondria play a key role in a variety of other processes believed to be important in cell death (Fig. 2). Mitochondria are crucial to intra cellular calcium homeostasis (Duchen, 2000), and possess several calcium transport systems (Nicholls, 1985). The concentration of free intracellular calcium is central to normal neuronal functioning, and in turn this has been shown to be critically dependent on functioning mitochondria, as well as secondarily on sodium/calcium exchange (White and Reynolds, 1995). Intramitochondrial calcium levels also have important regulatory functions, including direct influence on enzymes of the TCA cycle and consequent metabolic rate, which will be further discussed by Heinemann et al. (2002, this volume).

Finally, the MRC has long been recognized as the major source of free radicals in the cell (Cadenas et al., 1977). Free radicals are highly reactive oxygen species, which, unopposed, can damage all cell structures, including lipids, proteins and DNA (Halliwell and Gutteridge, 1985). Some radicals are toxic via secondary reactions, one of the most important being the production of the highly damaging peroxynitrite from nitric oxide and the superoxide radical. Mitochondria possess a calcium-dependent nitric oxide synthase, thus have the potential for per-

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Na+/Ca" ATPase

MPT Caspase activation

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