INCREASE OF FLUX CONTROL OF CYTOCHROME-C-OXIDASE IN COPPER-DEFICIENT MOTTLED BRINDLED MICE

The brindled mottled mouse (Mo-br), an animal model of the Menkes' cop per deficiency syndrome, was used for the investigation of changes in respiratory flux control associated with cytochrome c oxidase deficien cy in muscle. Enzymatic analysis of cardiac and skeletal muscles showe d an approximately 2-fold decrease in cytochrome c oxidase activity of brindled mutants in both types of muscles as compared with controls, The activities of NADH-cytochrome c oxidoreductase (respiratory chain segment I-III) and succinate-cytochrome c oxidoreductase (segment II-I II) were normal. Assessment of mitochondrial respiratory function was performed using chemically skinned musculus quadriceps or heart muscle fibers isolated from control and brindled mottled mice. In skeletal m uscle, there was no difference found in maximal rates of respiration, In the Mo-br hearts, this parameter was slightly lower than control, A lternately, the determination of flux control coefficients of cytochro me c oxidase performed by a step by step inhibition of respiration wit h increasing concentrations of azide or cyanide revealed significantly sharper inhibition curves for brindled mice than for control, indicat ing more than 2-fold elevated flux control coefficients of cytochrome c oxidase, This investigation proved essential in characterizing the m etabolic effect of a cytochrome c oxidase deficiency. We conclude, the refore, that application of metabolic control analysis can be a valuab le approach to study defects of mitochondrial oxidative phosphorylatio n.