Complex I Is Rate-limiting for Oxygen Consumption in the Nerve Terminal

Metabolic control analysis was used to determine the spread of control exerted by the electron transport chain complexes over oxygen consumption rates in the nerve terminal. Oxygen consumption rates and electron transport chain complex activities were titrated with appropriate inhibitors to determine the flux control coefficients and the inhibition thresholds in rat brain synaptosomes. The flux control coefficients for complex I, complex II/III, complex III, and complex IV were found to be 0.30 ± 0.07, 0.20 ± 0.03, 0.20 ± 0.05, and 0.08 ± 0.05, respectively. Inhibition thresholds for complex I, complex II/III, complex III, and complex IV activities were determined to be ∼10, ∼30, ∼35, and 50–65%, respectively, before major changes in oxygen consumption rates were observed. These results indicate that, of the electron transport chain components, complex I exerts a high level of control over synaptosomal bioenergetics, suggesting that complex I deficiencies that are present in neurodegenerative disorders, such as Parkinson disease, are sufficient to compromise oxygen consumption in the synaptosomal model of the nerve terminal.