We searched PubMed for articles published from Jan 1, 1980, to June 15, 2015, in English using the search terms “mitochondri* AND (epilep* OR seizur*)” and “mitochondri* mutation”. Further references were selected from the reference lists of relevant articles. We also searched the Online Mendelian Inheritance in Man database using the terms “mitochondria AND epilepsy” and “mitochondria AND seizure”, and the MitoPhenome database for “seizure”. The final reference list was generated on the basis
ReviewMitochondrial dysfunction and seizures: the neuronal energy crisis
Introduction
According to the classic view, seizures are the result of an imbalance between excitatory and inhibitory neuronal activities. Historically, epilepsy research focused on changes in synaptic transmission caused by dysfunction of ion channels and neurotransmitter receptors. However, advances in research in the past decade have unravelled the genetic cause of disorders associated with seizures, and an emerging body of evidence suggests that epilepsy has to be thought of in a much broader context. The long list of pathogenic mutations in the mitochondrial genome and in nuclear-encoded mitochondrial proteins manifesting in epileptic phenotypes clearly shows that mitochondrial dysfunction represents a primary cause of epilepsy. This finding is not surprising in view of the pivotal role of mitochondrial oxidative phosphorylation in the generation of the ATP needed for synaptic transmission and firing of action potentials. Additionally, mitochondria have a central role in neurotransmitter synthesis, calcium homoeostasis, redox signalling, production and modulation of reactive oxygen species (ROS), and neuronal death,1, 2, 3 and many of these processes might also be relevant for seizure generation. In acquired epilepsy, mitochondrial dysfunction has also been shown to coexist with epileptogenesis and chronic epilepsy. This coexistence has been explained by the finding that seizures themselves create a substantial challenge to energy metabolism,4 which triggers mitochondrial damage and secondary dysfunction. This highlights the relevance of the interdependency between mitochondrial function and seizures.
In this Review, we first summarise data from published work on genetically defined forms of epilepsy, which show that primary disturbances of almost any aspect of mitochondrial function can lead to seizures. We then address secondary changes in mitochondrial function in acquired forms of epilepsy and discuss potential general mechanisms that can link mitochondrial dysfunction to seizures. Finally, we outline possible approaches to the treatment of mitochondria-related epilepsy.
Section snippets
Bioenergetics in the CNS
The overall ATP turnover (30 μmol ATP/g tissue per min) in neuron-rich grey matter of the brain has been estimated to be similar to that in the leg muscle during a marathon,5 which explains why a tissue with a contribution of only 2% to bodyweight can make up more than 20% of resting whole-body metabolism.6 In this estimation, the firing of action potentials accounts for around 25% of energy consumption in the brain, and synaptic transmission contributes to most of the remaining energy
Mitochondrial DNA mutations
Many of the genetically determined cases of epileptic syndromes associated with mitochondrial dysfunction originate from pathogenic mutations in the mitochondrial genome. Mitochondrial DNA (mtDNA) codes for 13 key subunits of oxidative phosphorylation complexes and 24 RNA components needed for mitochondrial translation. Mutations in more than half of these genes have been reported in patients with epilepsy (appendix). The most frequent is the 8344A→G mutation in the MT-TK gene17 (encoding
Mutations in nuclear-encoded genes
Most mitochondrial proteins are encoded in the nucleus, and an increasing number of defects of these genes have been identified as a cause of mitochondrial dysfunction. In this section, we discuss nuclear mutations of mitochondrial proteins that have been reported to be associated with seizures (table; appendix). Epileptic seizures can be a presenting or late feature of these genetic defects, and almost any seizure semiology and combinations can occur, although classic absence seizures are very
Mitochondrial dysfunction in sporadic epilepsy
Mitochondrial dysfunction has been shown to coexist with seizure generation and chronic epilepsy not only in genetic forms of epilepsy but also in acquired epilepsy.73 This finding has been shown most clearly for hippocampal sclerosis, a common form of focal epilepsy, in which severely reduced activity of respiratory chain complex I has been reported for the CA3 hippocampal subfield.74 A typical histological feature of local mitochondrial dysfunction is the presence of cytochrome c
Mechanisms of seizure generation
Besides the genetic defects of oxidative phosphorylation, as discussed previously, chemical inhibition of specific complexes of the mitochondrial respiratory chain (eg, by direct brain injections of cyanide84 for cytochrome c oxidase or 3-nitropropionic acid85 for succinate dehydrogenase) also induces seizures. Since mitochondrial ATP production has a general effect on cellular function in many tissues, the question arises of which specific changes in neuronal function might be the primary
Therapeutic perspectives
Apart from some rare disorders—eg, primary coenzyme Q10 deficiencies (described previously), which can be successfully treated by coenzyme Q10 supplementation29—no general treatment concept for mitochondrial forms of epilepsy exists at present. Anecdotal reports have been provided on the beneficial effects of treatment with coenzymes of deficient enzyme complexes, such as riboflavin in β-oxidation and some complex I defects,103, 104 thiamine in defects of pyruvate oxidation,105 and nicotinamide
Conclusions and future directions
The development of new sequencing techniques that enable screening of pathogenic mutations in whole exomes or genomes123 has allowed identification of the underlying cause of a large subgroup of seizure disorders that are related to oxidative phosphorylation dysfunction. Until now, pathogenic mutations in 22 mtDNA-encoded genes and at least 147 nuclear-encoded mitochondrial genes have been reported to be associated with epileptic phenotypes. Widespread application of the new sequencing
Search strategy and selection criteria
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