Energy Thresholds in Brain Mitochondria

Abstract

Decreases in mitochondrial respiratory chain complex activities have been implicated in neurodegenerative disorders such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. However, the extent to which these decreases cause a disturbance in oxidative phosphorylation and energy homeostasis in the brain is not known. We therefore examined the relative contribution of individual mitochondrial respiratory chain complexes to the control of NAD-linked substrate oxidative phosphorylation in synaptic mitochondria. Titration of complex I, III, and IV activities with specific inhibitors generated threshold curves that showed the extent to which a complex activity could be inhibited before causing impairment of mitochondrial energy metabolism. Complex I, III, and IV activities were decreased by approximately 25, 80, and 70%, respectively, before major changes in rates of oxygen consumption and ATP synthesis were observed. These results suggest that, in mitochondria of synaptic origin, complex I activity has a major control of oxidative phosphorylation, such that when a threshold of 25% inhibition is exceeded, energy metabolism is severely impaired, resulting in a reduced synthesis of ATP. Additionally, depletion of glutathione, which has been reported to be a primary event in idiopathic Parkinson's disease, eliminated the complex I threshold in PC12 cells, suggesting that antioxidant status is important in maintaining energy thresholds in mitochondria. The implications of these findings are discussed with respect to neurodegenerative disorders and energy metabolism in the synapse.

Mitochondrial Respiration and ATP Production Are Significantly Impaired in Striatal Cells Expressing Mutant Huntingtin

“…However, variations in the complex I threshold in different brain mitochondria have already been demonstrated. It was found that synaptic rat brain mitochondria have complex I threshold of ϳ25% (48). Also in PC12 cells the threshold for complex I was ϳ7% (28), which is similar to what we observed in the striatal cells (Table II).…”

Oxidative α-Ketoglutarate Dehydrogenase Inhibition via Subtle Elevations in Monoamine Oxidase B Levels Results in Loss of Spare Respiratory Capacity

“…Dox-induced cells displayed a significant decrease in both activity of complex I as well as complex I substrate-mediated oxygen consumption compared with untreated controls. A previous report (61) suggested that a reduction of complex I activity by as little as 25% in isolated brain synaptosomes was sufficient to render a significant effect on complex I substrate-mediated respiration. We found that elevation of MAO-B levels by 2-3-fold in differentiated dopaminergic PC12 resulted in a 40% inhibition of complex I activity, akin to what is observed in PD patients (62)(63)(64), and a corresponding decrease in oxygen consumption rates.…”

Normal brain ageing: models and mechanisms

“…The danger in these conditions is that the multi-factorial nature of the coupling between the oxidative cycles of the respiratory chain and the adenosine disphosphate phosphorylation may lead to significant miscalculations. Thus, Davey et al showed that in rat brain synaptosomes, differential levels of inhibition of the complexes I, III and IV were required to induce significant decreases of ATP levels: while only 20% inhibition of the complex I was sufficient for the inhibition of ATP production, the complex III was much more resilient, and required a drastic inhibition of up to 80% to achieve the same block of ATP production (Davey et al 1998). It is also Figure 1.…”