How mitochondrial dysfunction can alter neuronal excitability ?

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Beside alterations of mitochondrial substrate oxidation and ATP synthesis due to disease-associated mutations discussed in detail before, also the direct partial inhibition of enzymes of mitochondrial respiratory chain – of cytochrome c oxidase by cyanide, and of succinate dehydrogenase by 3-nitropropionic acid – evoke seizures. Potential direct links between the observed impairment of mitochondrial function and the increased neuronal excitability causing epileptiform activity are (i) decreased intracellular ATP levels and (ii) alterations of neuronal calcium homeostasis. A relatively high impact of neuronal ATP levels can be postulated since epileptic seizures are observed in Leigh syndrome patients harbouring the mutations T8993G and T8993C in the ATPase 6 gene. Under these conditions mitochondria still have a high membrane potential enabling normal ion transport. Therefore, for cybrids with the T8993G NARP mutation normal mitochondrial calcium handling properties at decreased cellular ATP levels were observed. It has to be mentioned that mitochondrial oxidative phosphorylation provides the major source of ATP in neurons and adequate ATP levels are essential to maintain the neuronal plasma membrane potential via the sodium-potassium ATPase which consumes about 40% of the energy. Therefore, the decreased neuronal plasma membrane potential is most likely responsible for epileptic seizures observed in Leigh syndrome patients harbouring ATPase 6 gene mutations.

On the other hand it is well established that mitochondria are an important intracellular Ca²⁺ sequestration system. Especially due to this feature, mitochondria are believed to modulate neuronal excitability and synaptic transmission which is altered in epilepsy. In agreement with this concept in kainate-treated chronic epileptic rats impaired oxidative phosphorylation due to Ca²⁺ cycling at the inner membrane of hippocampal mitochondria has been demonstrated by us. Similarly, impaired cellular Ca²⁺ homeostasis due to substantial alterations of mitochondrial Ca²⁺ handling was the predominant feature of cybrid cells harbouring the mitochondrial T8356C mutation being associated with MERRF.