The model of the respiratory chain in which the enzyme complexes are independently embedded in the lipid bilayer of the inner mitochondrial membrane and connected by randomly diffusing coenzyme Q and cytochrome c is mostly favored. However, multicomplex units can be isolated from mammalian mitochondria, suggesting a model based on direct electron channeling between complexes. Kinetic testing using metabolic flux control analysis can discriminate between the two models: the former model implies that each enzyme may be rate-controlling to a different extent, whereas in the latter, the whole metabolic pathway would behave as a single supercomplex and inhibition of any one of its components would elicit the same flux control. In particular, in the absence of other components of the oxidative phosphorylation apparatus (i.e. ATP synthase, membrane potential, carriers), the existence of a supercomplex would elicit a flux control coefficient near unity for each respiratory complex, and the sum of all coefficients would be well above unity. Using bovine heart mitochondria and submitochondrial particles devoid of substrate permeability barriers, we investigated the flux control coefficients of the complexes involved in aerobic NADH oxidation (I, III, IV) and in succinate oxidation (II, III, IV). Both Complexes I and III were found to be highly rate-controlling over NADH oxidation, a strong kinetic evidence suggesting the existence of functionally relevant association between the two complexes, whereas Complex IV appears randomly distributed. Moreover, we show that Complex II is fully rate-limiting for succinate oxidation, clearly indicating the absence of substrate channeling toward Complexes III and IV.Considerable information exists on the structure at atomic resolution of most of the transmembrane protein complexes forming the mitochondrial respiratory chain; there is, however, still little direct information on the supramolecular organization of the enzymatic complexes in the inner mitochondrial membrane. Two extreme models for their arrangement in the membrane are conceivable: the model of a random organization of the individual respiratory complexes and that of a supercomplex assembly formed by stable association between proteins.The original solid-state model of Chance and Williams (1) changed gradually because the oxidative phosphorylation enzymes were found functionally active when isolated as individual complexes (2) Despite the acceptance of the idea that electron transfer in mitochondrial membranes depends on random collisions between small diffusing molecules (coenzyme Q and cytochrome c) and complexes
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