The Influence And Mechanism Of Neuron Mitothondrial Electron Transport Chain Complex Inhibition On Persistent And Transient Sodium Currents

In the initial stages of hypoxia, it has been known that cells undergo alterations in mitochondrial respiratory chain, membrane ion channels, neurotransmitters release, intracellular environment and gene expression, etc. Among them, the alterations in mitochondrial respiratory chain are one focus of study. The inhibition of the complex I. complex II,complex III and complex IV of the mitochondrial respiratory chain during hypoxia has been observed in different studies. However, the downstream signaling pathways of these inhibition remain to be studied. The present paper used the complex I inhibitor rotenone. the complex II inhibitor TTFA (TTFA: thenoyltrifluoroacetone). the complex III oxidation center inhibitor myxothiazol, the complex III reduction center inhibitor antimycin A and the ATP synthase inhibitor oligomycin to mimic the inhibition of mitochondrial electron transport complex and studied the effects of these inhibition on persistent sodium currents (Inap), transient sodium currents (I_NaT) and neuronal excitability in rat hippocampal CA1 cells in slices and in acutely dissociated cells using whole cell patch-clamp methods. Moreover, we further analyzed their possible mechanisms using pharmacological approaches and biochemical technique. The results showed (1) that the complex I inhibitor rotenone, the complex II inhibitor TTFA and the ATP synthase inhibitor oligomycin had no apparent effects on I_Nap. However, the complex III oxidation center inhibitor myxothiazol significantly increased I_nap- whereas the complex III reduction center inhibitor antimycin A apparently decreased I_nap- The mitochondrial anion channel blocker DIDS alone did not have effects on I_nap. In the presence of DIDS, the increasing effect of myxothiazol on I_nap was blocked, but the decreasing effect of antimycin A was reversed. The decreasing effect of antimycin A could be cancelled by pretreatment with the antioxidant 2-mercaptopropionylglycine or 1,10 phenanthroline and H2O2 could mimic the effect of antimycin A. The increasing effect of myxothiazol was blocked by the protein kinase C inhibitor chelerythrine and protein kinase C activity is significantly increased by myxothiazol, but the antioxidant 2-mercaptopropionylglycine or 1,10 phenanthroline had no significantly influence on the effect of myxothiazol.(2) The complex III reduction center inhibitor antimycin A...