Altered mitochondrial oxidative phosphorylation in hippocampal slices of kainate-treated rats.

Mitochondria provide the main neuronal energy supply and are important organelles for the sequestration of intracellular Ca2+. This indicates a possible important role for mitochondria in modulating neuronal excitability in normal function as well as in disease. Therefore, we have investigated mitochondrial oxidative phosphorylation in the kainate model of epilepsy. We measured the oxygen consumption of single 400-micron rat hippocampal slices applying high resolution respirometry and determined mitochondrial NAD(P)H autofluorescence signal changes in single slices by laser-excited fluorescence spectroscopy. We observed an about 2-fold higher (p<0.001) basal glucose oxidation rate in slices from kainate-treated animals. This increased endogenous energy consumption was found to be unrelated to spontaneous activity since it was not sensitive to the inhibitors of the sodium-potassium ATPase ouabain and of the mitochondrial adenine nucleotide translocator atractyloside. This finding suggested an increased mitochondrial energy turnover in kainate-induced epilepsy. Furthermore, the uncoupler-stimulated oxygen consumption of the slices was approximately 1.3-fold higher (p<0.01) in the kainate model. In accordance with the respirometric data, fluorescence spectroscopy showed decreased reduction levels of the mitochondrial NAD-system in glucose oxidizing slices from kainate-treated rats. The preincubation of epileptic hippocampal slices with either BAPTA AM, ruthenium red or TPP+ increased the atractyloside sensitivity of glucose oxidation to about 1.4-fold (p<0.01). These observations indicate that the increased mitochondrial energy turnover in hippocampal slices from kainate-treated rats is most possibly caused by futile Ca2+-cycling.