Dysfunction of the mitochondrial respiratory chain associated with epilepsy

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Mitochondrial oxidative phosphorylation provides the major source of ATP in neurons. It consists of five multienzyme complexes located in the mitochondrial inner membrane (Figure). The complexes I to IV are oxidoreductases which participate in the transfer of reducing equivalents from NADH and FADH₂ to oxygen and create an electrochemical proton gradient across the mitochondrial inner membrane. Complex V – the F₀F₁-ATPase - uses this proton gradient for the synthesis of ATP. Defects of oxidative phosphorylation in the CNS are the characteristic sign of mitochondrial encephalopathies. In a broad variety of these diseases epileptic seizures have been observed. An overview of the most common mitochondrial disorders presenting with an epileptic phenotype is given in the Table. Most of them are associated with mutations in the autonomous mitochondrial DNA, consisting of 13 polypeptide genes, a 16S and a 12S rRNA gene and 22 tRNA genes. A well known mitochondrial disorder with an epileptic phenotype is the MERRF (myoclonus epilepsy with ’ragged red fibers’) syndrome which has been associated with mutations in the mitochondrial tRNA^Lys gene. However, as shown in the Table, other mitochondrial DNA mutations predominantly localised in the mitochondrial tRNA genes for lysin, serin, leucin, isoleucin or cystein have been also associated with epileptic phenotypes. These mutations affect the protein biosynthesis of all mitochondrial-encoded subunits of the following complexes of the mitochondrial oxidative phosphorylation pathway: complex I (NADH:CoQ oxidoreductase, containing 7 mitochondrial-encoded subunits), complex III (CoQH₂:cytochrome c oxidoreductase, containing 1 mitochondrial-encoded subunit), complex IV (cytochrome c oxidase, containing 3 mitochondrial-encoded subunits) and complex V (F₀F₁-ATPase, containing 2 mitochondrial-encoded subunits). Quite rarely, also mutations in polypeptide-coding mitochondrial genes have been reported in patients with epilepsy – in the ATPase 6 gene, in the CO III gene and in the ND 1 gene. We have recently identified a novel mutation in the CO I gene associated with Epilepsia patialis continua.

The large variation in the clinical phenotype, even for a given mutation, is a well known feature of mitochondrial diseases. It is therefore very likely that the distribution of the mitochondrial defect within the CNS is the responsible factor which determines the association of a certain mutation with epilepsy. Thus KSS is almost a white matter disorder affecting preferentially brainstem tegmentum, white matter of cerebellum and cerebrum, cervical spinal cord, basal ganglia, and diencephalon. On the other hand, MELAS is characterised by foci of necrosis, which are predominantly localised in the cerebral cortex and also in the hippocampus – a highly epileptogenic area, whereas MERRF involves preferentially the inferior olivary nucleus, the cerebellar dentate nucleus, the red necleus and the pontine tegmentum – structures being implicated in the genesis of myoclonus.

In contrast to the relatively rare mitochondrial encephalopathies being associated with mtDNA mutations epilepsy is a frequent neurological disorder usually well controlled by presently available drugs. However, 20 to 30% of patients do not experience seizure control with available medication. The majority of these patients suffer from focal epilepsies which frequently develop subsequently to brain trauma, complicated febrile convulsions, status epilepticus, ischemic lesions and brain tumours. The areas of epileptogenesis in these cases are usually characterised by cell loss. It is well documented that during seizures both nerve cells and glia undergo necrotic and apoptotic cell death. Neuropathological investigations have repeatedly pointed to a similarity between ischemic and seizure related alterations of neurons characterised by swollen and often disrupted mitochondria. In patients with Ammon’s horn sclerosis mitochondrial ultrastructural pathology was described as characteristic feature of hilar neurons. In this context is noteworthy to mention, that in addition to the pathological abnormalities also functional defects of mitochondria have been reported in the areas of epileptogenesis. Thus, we observed a severe impairment of respiratory chain complex I activity for CA3 neurons in the hippocampus from patients with Ammon’s horn sclerosis and in the parahippocampal gyrus of patients with parahippocampal lesions. In these reports the mitochondrial abnormalities have been observed only close to or directly in the epileptic focus, while the investigated surrounding brain tissue (e.g. the parahippocampal gyrus of patients with a clearly pronounced hippocampal pathology and a hippocampal seizure focus) showed now mitochondrial pathology.