ENERGY THRESHOLDS IN BRAIN MITOCHONDRIA - POTENTIAL INVOLVEMENT IN NEURODEGENERATION

Decreases in mitochondrial respiratory chain complex activities have b een implicated in neurodegenerative disorders such as Parkinson's dise ase, Huntington's disease, and Alzheimer's disease, However, the exten t to which these decreases cause a disturbance in oxidative phosphoryl ation and energy homeostasis in the brain is not known. We therefore e xamined the relative contribution of individual mitochondrial respirat ory chain complexes to the control of NAD-linked substrate oxidative p hosphorylation 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 TV activities were decreased by approximately 25, 80, and 70%, respectively, before major changes in rates of oxygen consumption and ATP synthesis mere observed. These results suggest that, in mitoc hondria of synaptic origin, complex I activity has a major control of oxidative phosphorylation, such that when a threshold of 25% inhibitio n is exceeded, energy metabolism is severely impaired, resulting in a reduced synthesis of ATP. Additionally, depletion of glutathione, whic h has been reported to be a primary event in idiopathic Parkinson's di sease, eliminated the complex I threshold in PC12 cells, suggesting th at antioxidant status is important in maintaining energy thresholds in mitochondria. The implications of these findings are discussed with r espect to neurodegenerative disorders and energy metabolism in the syn apse.