The effect of rotenone on the regulation of fatty acid synthesis in heart mitochondria.

Acetate-lJ*C incorporation into long chain fatty acids by rabbit heart mitochondria was increased up to ZO-fold by citrate, isocitrate, malate, or succinate in the presence of rotenone and ATP. Rotenone blocked NADH oxidation and enabled the maintenance of a high NADH:NAD+ ratio. The rate of fatty acid synthesis was linearly related to the resulting endogenous mitochondrial NADH : NAD+ ratio. By inhibiting reversed electron flow, rotenone inhibited the early high rate of acetate incorporation observed with succinate oxidation. In this situation, succinate supplied reducing equivalents for fatty acid synthesis via malate dehydrogenase. Rotenone also blocked the ADPor dinitrophenol-induced cleavage of newly incorporated acetate-lJ*C from mitochondrial fatty acids by preventing a decrease in the NADH: NAD+ ratio. The NAD oxidation-reduction state is concluded to be the regulator of the rate and direction of the heart mitochondrial fatty acid synthetic-oxidation system.