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Review
. 2010 Jan;88(1):23-45.
doi: 10.1016/j.eplepsyres.2009.09.020. Epub 2009 Oct 21.

Mitochondria, oxidative stress, and temporal lobe epilepsy

Simon Waldbaum  1 , Manisha Patel
Affiliations
Review

Mitochondria, oxidative stress, and temporal lobe epilepsy

Simon Waldbaum et al. Epilepsy Res. 2010 Jan.

Abstract

Mitochondrial oxidative stress and dysfunction are contributing factors to various neurological disorders. Recently, there has been increasing evidence supporting the association between mitochondrial oxidative stress and epilepsy. Although certain inherited epilepsies are associated with mitochondrial dysfunction, little is known about its role in acquired epilepsies such as temporal lobe epilepsy (TLE). Mitochondrial oxidative stress and dysfunction are emerging as key factors that not only result from seizures, but may also contribute to epileptogenesis. The occurrence of epilepsy increases with age, and mitochondrial oxidative stress is a leading mechanism of aging and age-related degenerative disease, suggesting a further involvement of mitochondrial dysfunction in seizure generation. Mitochondria have critical cellular functions that influence neuronal excitability including production of adenosine triphosphate (ATP), fatty acid oxidation, control of apoptosis and necrosis, regulation of amino acid cycling, neurotransmitter biosynthesis, and regulation of cytosolic Ca(2+) homeostasis. Mitochondria are the primary site of reactive oxygen species (ROS) production making them uniquely vulnerable to oxidative stress and damage which can further affect cellular macromolecule function, the ability of the electron transport chain to produce ATP, antioxidant defenses, mitochondrial DNA stability, and synaptic glutamate homeostasis. Oxidative damage to one or more of these cellular _targets may affect neuronal excitability and increase seizure susceptibility. The specific _targeting of mitochondrial oxidative stress, dysfunction, and bioenergetics with pharmacological and non-pharmacological treatments may be a novel avenue for attenuating epileptogenesis.

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Figures

Fig. 1
Fig. 1
Mitochondrial function and neuronal excitability. Various aspects of the mitochondria can lead to impairment of its bioenergetic capacity affecting neuronal excitability, apoptosis, and an increase in seizure susceptibility. O2·− production by complex I and III of the ETC leads to the production of ONOO− in a reaction with NO, and H2O2 through dismutation by the antioxidant MnSOD (SOD2). H2O2 is membrane permeable and able to diffuse out of the mitochondria causing widespread oxidative damage. Excessive O2·− production also damages Fe-S containing enzymes involved in the TCA cycle such as aconitase. OH· can be formed from H2O2 through Fenton chemistry and lead to further oxidative damage of macromolecules such as ETC complexes and mtDNA. Oxidative damage to mtDNA can lead to increased mutation rates and a decrease in ETC subunit expression encoded by the mitochondrial genome. Alterations in the redox status of GSH/GSSG and CoASH/CoASSG can cause an inability to protect against the deleterious effects of ROS. Modification of neurotransmitter biosynthesis within the mitochondria can affect levels of neuronal excitability/inhibition. Oxidative damage to these _targets can result in increased neuronal excitability resulting from decreased mitochondrial membrane potential and ATP levels affecting the Na+/K+ ATPase and the release of cyto C leading to apoptosis. mNa+C2+E=mitochondrial sodium calcium exchanger; mCU=mitochondrial calcium uniporter; mNICE=mitochondrial sodium independent calcium exchanger; MPT=mitochondrial permeability transition pore; GSH=glutathione; GSSG=glutathione disulfide; CoASH=coenzyme A; CoASSG=coenzyme A glutathione disulfide; GR=glutathione reductase; GPx=glutathione peroxidase; cyto C=cytochrome C; Ψm=mitochondrial membrane potential.
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