The Role of Succinate in the Regulation of Fatty Acid Synthesis by Heart Mitochondria

Rabbit heart mitochondria have a very active fatty acid-synthetic system. The system has a much greater capacity than similarly isolated mitochondria from liver or kidney, and is presumed to have special functional significance for heart. The system yields a mixture of products: shorter (12 to 16 carbon atoms) chain fatty acids are synthesized de novo from acetate, and longer chain fatty acids result from the elongation of preformed acyl units. Evidence is presented that the rate of synthesis is controlled by the NADH:NAD+ ratio and that stimulation of synthesis by Krebs cycle acids only occurs when there is a marked increase in the ratio. Succinate has an extraordinary capacity to stimulate the system, and the mechanism by which this is accomplished is via reversed electron flow. This, therefore, is an important physiological role of reversed electron flow from succinate. When the NADH:NAD+ ratio decreases rapidly, such as in State 3, fatty acid oxidation commences, including oxidation of the recently synthesized fatty acids. It is postulated that the synthetic system is the reversal of the oxidation process and that there is present, therefore, a fatty acid oxidation-synthesis cycle. The rate of activity of this cycle in either direction is controlled by the NADH:NAD+ ratio. On the basis of the present experiments, the concept has been developed that the mitochondrial fatty acid-synthetic pathway represents a storage form of acetyl units during the development of debt. When oxygen is again readily available, these acetyl units are oxidized to yield energy.