Metabolism of propionate by sheep-liver mitochondria. Evidence for rate control by a specific succinate oxidase.

1. Metabolism of propionate by sheep-liver mitochondria was stimulated catalytically by alpha-oxoglutarate, pyruvate, citrate and isocitrate. Succinate was stimulatory at higher concentrations, but fumarate and malate were inert. These effects were all independent of the presence of ATP, succinate being less effective when ATP was present. 2. Compared with the metabolism of added succinate, propionate metabolism was resistant to malonate inhibition, but only in the presence of added ATP. In the absence of ATP propionate metabolism was more sensitive to malonate inhibition than was the metabolism of succinate. 3. In the absence of malonate, and at malonate concentrations in the range 5-100mm, alpha-oxoglutarate increased the rate of fixation of [2-(14)C]propionate by about 50% without altering the nature of the fixation products. 4. Metabolism of [1-(14)C]-propionate in the presence of 50mm-malonate was accompanied by accumulation of about half the propionate consumed as succinate. When alpha-oxoglutarate was present in addition part of the alpha-oxoglutarate was metabolized and the rate of propionate consumption was increased. The total succinate that accumulated corresponded to the alpha-oxoglutarate consumed plus about half the propionate metabolized. 5. When [1-(14)C]propionate was metabolized in the absence of malonate about 70% of the generated succinate was oxidized to fumarate or beyond. The addition of malonate decreased the rate of propionate metabolism, and decreased to about half the fraction of generated succinate oxidized. 6. When propionate and 10mm-succinate were metabolized together, the total oxidation of succinate was greater than that with 10mm-succinate alone. The increment in succinate oxidation corresponded to about half the propionate metabolized in the presence or absence of malonate or ATP. 7. It is suggested that the metabolism of propionate is specifically limited by the rate of oxidation of the generated succinate, and that the succinate oxidase concerned is distinct from that responsible for the oxidation of added succinate. 8. The results are discussed in terms of the mode of action of certain stimulants and inhibitors of propionate metabolism. It is suggested that many of these act by stimulation or inhibition of the specific succinate oxidase that limits propionate metabolism.