Abstract
BackgroundThe activities of mitochondrial complex III (ubiquinol-cytochrome c reductase, EC 1.10.2.2) and complex IV (cytochrome c oxidase EC 1.9.3.1) are reduced by 30-70% in Huntington's disease and Alzheimer's disease, respectively, and are associated with excitotoxic cell death in these disorders. In this study, we investigated the control that complexes III and complex IV exert on glutamate release from the isolated nerve terminal.ResultsInhibition of complex III activity by 60-90% was necessary for a major increase in the rate of Ca2+-independent glutamate release to occur from isolated nerve terminals (synaptosomes) depolarized with 4-aminopyridine or KCl. Similarly, an 85-90% inhibition of complex IV activity was required before a major increase in the rate of Ca2+-independent glutamate release from depolarized synaptosomes was observed. Inhibition of complex III and IV activities by ~ 60% and above was required before rates of glutamate efflux from polarized synaptosomes were increased.ConclusionsThese results suggest that nerve terminal mitochondria possess high reserves of complex III and IV activity and that high inhibition thresholds must be reached before excess glutamate is released from the nerve terminal. The implications of the results in the context of the relationship between electron transport chain enzyme deficiencies and excitotoxicity in neurodegenerative disorders are discussed.
Highlights
IntroductionThe activities of mitochondrial complex III (ubiquinol-cytochrome c reductase, EC 1.10.2.2) and complex IV (cytochrome c oxidase EC 1.9.3.1) are reduced by 30-70% in Huntington’s disease and Alzheimer’s disease, respectively, and are associated with excitotoxic cell death in these disorders
The activities of mitochondrial complex III and complex IV are reduced by 30-70% in Huntington’s disease and Alzheimer’s disease, respectively, and are associated with excitotoxic cell death in these disorders
Glutamate excitotoxicity is thought to occur in chronic neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis [1,2], and dysfunction of mitochondrial electrion transport chain complexes have been implicated in the pathogenesis of these diseases [3,4,5]
Summary
The activities of mitochondrial complex III (ubiquinol-cytochrome c reductase, EC 1.10.2.2) and complex IV (cytochrome c oxidase EC 1.9.3.1) are reduced by 30-70% in Huntington’s disease and Alzheimer’s disease, respectively, and are associated with excitotoxic cell death in these disorders. We investigated the control that complexes III and complex IV exert on glutamate release from the isolated nerve terminal. A decrease in complex IV activity in the brain associated with aging is thought to occur [16,17,18] and insufficient control over glutamate release due to mitochondrial complex III and IV deficiency are thought to contribute to neuronal cell death [8,19]. The resulting increase in extracellular glutamate concentration causes post-synaptic glutamate receptor overactivation, resulting in Ca2+
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
