Mitochondrial Dysfunction in Epilepsy
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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Epilepsy: Mitochondrial connections to the ‘Sacred’ disease
2023, MitochondrionCirculating malondialdehyde level in patients with epilepsy: A meta-analysis
2022, SeizureCitation Excerpt :Oxidative stress increases neuronal excitability and this may increase susceptibility to epileptic seizures by affecting the intracellular balance of calcium, making the nervous system vulnerable to additional stress and neuronal cell loss [3,4]. Studies have shown that increased levels of reactive oxygen species (ROS) have been detected in models of epilepsy induced by pilocarpine and kainic acid [5,6]. Excessive ROS levels and decreased antioxidant defense ability lead to oxidative stress [7].
Effect of acute mitochondrial dysfunction on hyperexcitable network activity in rat hippocampus in vitro
2021, Brain ResearchCitation Excerpt :Recently, a new in vitro model of mitochondrial epilepsy was developed based on inhibition of the mitochondrial respiratory complex I (MRCI) and complex IV (MRCIV) in addition to specific inhibition of the astrocytic aconitase (Chan et al., 2019). Even in acquired epilepsy, the metabolic stress imposed by seizure activity can lead to mitochondrial damage and secondary dysfunction which has been argued to contribute to epilepto- and ictogenic processes (for review see Khurana et al., 2013; Kudin et al., 2002; Liang and Patel, 2006; Rowley and Patel, 2013; Waldbaum and Patel, 2010; Zsurka and Kunz, 2015). Indeed, seizure activity in rats has been shown to downregulate the expression of enzymes involved in OXPHOS in area CA3 and CA1 of the hippocampus, and dysfunction of MRCI has been reported in patients with temporal lobe epilepsy (Kudin et al., 2002; Kunz et al., 2000).