Oxygen dependence of flux control of cytochrome c oxidase -- implications for mitochondrial diseases.

The oxygen dependence of cytochrome c oxidase control on succinate oxidation was investigated in saponin-permeabilized muscle fibers and isolated mitochondria from mouse quadriceps muscle applying metabolic control analysis. For this cyanide titrations of the oxygen consumption in the presence of succinate+rotenone were performed at different oxygen concentrations in the medium. While with isolated mitochondria high flux control coefficients were detected only at oxygen concentrations close to the KM value of cytochrome c oxidase, with saponin-permeabilized fibers a significant increase of cytochrome c oxidase flux control was already observed below 130 microM oxygen. The result is in line with the high oxygen sensitivity of maximal respiration of saponin-permeabilized muscle fibers (P50 = 33 microM) caused most probably by oxygen diffusion gradients through the fiber lattice. The oxygen dependence of cytochrome c oxidase flux control in muscle fibers can explain the pathological phenotype of mild cytochrome c oxidase deficiencies in mitochondrial myopathies.