Metabolic Consequences of the CytochromecOxidase Deficiency in Brain of Copper‐Deficient MovbrMice

Abstract:Biochemical micromethods were used for the investigation of changes in mitochondrial oxidative phosphorylation associated with cytochromecoxidase deficiency in brain cortex from Movbr(mottled viable brindled) mice, an animal model of Menkes’ copper deficiency syndrome. Enzymatic analysis of cortex homogenates from Movbrmice showed an approximately twofold decrease in cytochromecoxidase and a 1.4‐fold decrease in NADH:cytochromecreductase activities as compared with controls. Assessment of mitochondrial respiratory function was performed using digitonin‐treated homogenates of the cortex, which exhibited the main characteristics of isolated brain mitochondria. Despite the substantial changes in respiratory chain enzyme activities, no significant differences were found in maximal pyruvate or succinate oxidation rates of brain cortex homogenates from Movbrand control mice. Inhibitor titrations were used to determine flux control coefficients of NADH:CoQ oxidoreductase and cytochromecoxidase on the rate of mitochondrial respiration. Application of amobarbital to titrate the activity of NADH:CoQ oxidoreductase showed very similar flux control coefficients for control and mutant animals. Alternately, titration of respiration with azide revealed for Movbrmice significantly sharper inhibition curves than for controls, indicating a more than twofold elevated flux control coefficient of cytochromecoxidase. Owing to the reserve capacity of respiratory chain enzymes, the reported changes in activities do not seem to affect whole‐brain high‐energy phosphates, as observed in a previous study using31P NMR.