Mitochondrial Dysfunction in Epilepsy

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Epilepsy is the most common neurologic disorder worldwide and is characterized by recurrent unprovoked seizures. The mitochondrial (mt) respiratory chain is the final common pathway for cellular energy production through the process of oxidative phosphorylation. As neurons are terminally differentiated cells that lack significant regenerative capacity and have a high energy demand, they are more vulnerable to mt dysfunction. Therefore, epileptic seizures have been well described in several diseases such as mt encephalomyopathy, lactic acidosis, and stroke-like episodes and myoclonic epilepsy and ragged red fibers, which are caused by gene mutations in mtDNA, among others. Mutations in nuclear DNA regulating mt function are also being described (eg, POLG gene mutation). The role of mitochondria (mt) in acquired epilepsies, which account for about 60% of all epilepsies, is equally important but less well understood. Oxidative stress is one of the possible mechanisms in the pathogenesis of epilepsy resulting from mt dysfunction gradually disrupting the intracellular Ca2+ homeostasis, which modulates neuronal excitability and synaptic transmission, making neurons more vulnerable to additional stress, and leading to energy failure and neuronal loss in epilepsy. Antiepileptic drugs (AEDs) also affect mt function in several ways. There must be caution when treating epilepsy in patients with known mt disorders as some AEDs are toxic to the mt. This review summarizes our current knowledge of the effect of mt disorders on epilepsy, of epileptic seizures on mt, and of AEDs on mt function and the implications of all these interactions for the management of epilepsy in patients with or without mt disease.

Section snippets

Effect of Mitochondrial Disorders on Epilepsy

Epilepsy can be seen in disorders caused by mutations in mtDNA and nuclear genes. The best known syndromes due to mtDNA mutations are Leigh disease, MELAS, MERRF, Leber hereditary optic neuropathy, and Kearns-Sayre syndrome and the best known nuclear DNA mutations are in the POLG gene encoding the catalytic subunit of the mtDNA polymerase. However, there are other well-described syndromes with associated epilepsy, and new mutations are almost constantly being described (Table 1, Table 2).

Pathogenetic Mechanisms Underlying the Relationship of Mitochondria and Epilepsy

Is mt dysfunction or epilepsy the cause or consequence? Although the answer is still controversial, it is likely that they may be closely interrelated to create a vicious cycle9 (Fig. 1).

Effect of Antiepileptic Drugs on Mitochondrial Function

AEDs are the main method of treatment of epilepsy. With the increasing number of AEDs available to treat seizures and epilepsy, it is important to be aware of the various side effects and changes they can cause in the body and its metabolic pathways. This is particularly true for patients with mt disorders as some AEDs may be mt toxic and may worsen the disorder itself.8, 16

Correction of Mitochondrial Respiratory Chain Complex Deficiencies

During the past few years, a significant amount of basic research has been directed toward developing pharmacologic approaches to restore mt function.70, 71 Although the molecular understanding of the underlying mechanisms is poor, several clinical studies have demonstrated that it may be possible to pharmacologically stimulate mt biogenesis and promote the correction of mt respiratory chain complex deficiencies.28 Because COX (cytochrome c oxidase) plays a central role in the mt respiratory

Conclusion

There is a bidirectional relationship between epilepsy and mt function. Mt disorders, due to mutations in the genes in mtDNA or nuclear DNA, frequently have epileptic seizures as a manifestation of the associated encephalopathy. On the contrary, epilepsy has a negative effect on mt function. It is likely that both are closely interrelated to create a vicious cycle, perpetuating mt dysfunction and epileptogenesis. OS has recently been demonstrated to be one of the possible mechanisms in such a

Acknowledgements

Supported in part by Grants from the St. Christopher's Foundation (St. Christopher's Hospital for Children), PHEC (Philadelphia Health Education Corporation), and DUCOM (Drexel University College of Medicine), Philadelphia, PA.

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