Fig. 3.

Mitochondrial function and neuronal excitability. Various aspects of the mitochondria can lead to impairment of its bioenergetic capacity affecting neuronal excitability, apoptosis, and an increase in seizure susceptibility. O₂·, production by complex I and III of the ETC leads to the production of ONOO⁻, in a reaction with NO, and H₂O₂ through dismutation by the antioxidant MnSOD (SOD2). H₂O₂ is membrane-permeable and able to diffuse out of the mitochondria causing widespread oxidative damage. Excessive O₂·, production also damages Fe-S-containing enzymes involved in the TCA cycle such as aconitase. OH· can be formed from H₂O₂ through Fenton chemistry and lead to further oxidative damage of macromolecules such as ETC complexes and mtDNA. Oxidative damage to mtDNA can lead to increased mutation rates and a decrease in ETC subunit expression encoded by the mitochondrial genome. Alterations in the redox status of GSH/GSSG and CoASH/CoASSG can cause an inability to protect against the deleterious effects of ROS. Modification of NT biosynthesis within the mitochondria can affect levels of neuronal excitability/inhibition. Oxidative damage to these targets can result in increased neuronal excitability resulting from decreased ΔΨ and ATP levels affecting the Na⁺/K⁺-ATPase and the release of cytochrome C, leading to apoptosis. mNa⁺C²⁺E, mitochondrial sodium calcium exchanger; mCU, mitochondrial calcium uniporter; mNICE, mitochondrial sodium independent calcium exchanger; CoASSG, CoA glutathione disulfide; GR, glutathione reductase; GPx, glutathione peroxidase; cytoC, cytochrome C; Suc, succinate; Fum, fumarate. Reprinted with permission (181).