Summary
The aim of this work was to establish the reasons why ketone bodies, although readily oxidized, do not sustain a physiological work output of the isolated rat heart for more than 30 to 45 min (Taegtmeyer, H., et al., Biochem. J.186, 701–711 (1980)). First, it was found that the addition of glucose or of asparagine increased the rate of acetoacetate removal by 52 and 77% respectively, and availability of oxaloacetate was one factor limiting the oxidation of acetoacetate. Second, in freeze clamped hearts perfusion with acetoacetate alone caused an increase in the tissue content of acetyl-CoA, citrate, 2-oxoglutarate and glutamate but no change in malate and a decrease in aspartate when compared with glucose as substrate. The changes of aspartate and glutamate exceeded those of 2-oxoglutarate forty times. This means that oxaloacetate formed from aspartate must have passed through the stages of the citric acid cycle to form glutamate and that there was an inhibition of the 2-oxoglutarate dehydrogenase reaction. Third, in hearts perfused with acetoacetate and propionate the accumulation of glutamate and 2-oxoglutarate as well as the decrease in aspartate were associated with a sharp drop in CoASH from 0.258 to 0.093 μmol/g dry wt. This indicates that the accumulation of CoA thioesters left insufficient mitochondrial CoASH for the 2-oxoglutarate dehydrogenase reaction. Fourth, in contrast to acetoacetate cardiac function was unimpaired with acetate plus glucose. With these substrates citrate, 2-oxoglutarate, malate and aspartate all accumulated, either due to formation of oxaloacetate by pyruvate carboxylase or transamination of glutamate with pyruvate. It appears that the changes in cardiac performance and metabolism caused by acetoacetate can be explained by a relative inhibition of the citric acid cycle at the level of 2-oxoglutarate dehydrogenase. The hypothesis is advanced that this might be due to a shortage of intramitochondrial free [CoASH], but the exact mechanism of this inhibition awaits further elucidation.
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Taegtmeyer, H. On the inability of ketone bodies to serve as the only energy providing substrate for rat heart at physiological work load. Basic Res Cardiol 78, 435–450 (1983). https://doi.org/10.1007/BF02070167
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DOI: https://doi.org/10.1007/BF02070167