Russell R R, Taegtmeyer H
Department of Medicine, University of Texas Medical School, Houston 77030.
J Clin Invest. 1992 Mar;89(3):968-73. doi: 10.1172/JCI115679.
Previous studies have indicated that ketone body-mediated contractile failure in rat hearts is due to inhibition of 2-oxoglutarate dehydrogenase, and it has been speculated that this inhibition is due to the sequestration of intramitochondrial CoA as acetoacetyl-CoA and acetyl-CoA. These studies were performed to determine whether oxidation of acetoacetate by isolated rat heart mitochondria results in a fall in intramitochondrial nonesterified CoA [CoASH] and whether increasing the available CoA improves contractile performance in hearts oxidizing acetoacetate. The oxidation of acetoacetate by isolated rat heart mitochondria resulted in depressed state 3 respiration as well as in a decrease in [CoASH]. Increasing the tissue content of CoASH in perfused hearts by providing the precursors for CoA relieved inhibition of 2-oxoglutarate dehydrogenase and improved the contractile performance of isolated working hearts. In contrast, the addition of carnitine increased the tissue content of CoASH but did not improve function. These findings suggest the presence of two different pools of CoASH. We conclude that ketone body-mediated inhibition of 2-oxoglutarate dehydrogenase is due to decreased intramitochondrial CoASH and that this inhibition of the citric acid cycle is a plausible mechanism for concomitant contractile failure.
以往的研究表明，大鼠心脏中酮体介导的收缩功能衰竭是由于2-氧代戊二酸脱氢酶受到抑制，并且据推测这种抑制是由于线粒体内的辅酶A（CoA）以乙酰乙酰辅酶A和乙酰辅酶A的形式被隔离。进行这些研究是为了确定离体大鼠心脏线粒体对乙酰乙酸的氧化是否会导致线粒体内非酯化辅酶A（CoASH）水平下降，以及增加可利用的辅酶A是否能改善氧化乙酰乙酸的心脏的收缩性能。离体大鼠心脏线粒体对乙酰乙酸的氧化导致状态3呼吸抑制以及CoASH水平降低。通过提供辅酶A的前体来增加灌注心脏中CoASH的组织含量，可缓解2-氧代戊二酸脱氢酶的抑制，并改善离体工作心脏的收缩性能。相比之下，添加肉碱可增加CoASH的组织含量，但并未改善功能。这些发现表明存在两种不同的CoASH池。我们得出结论，酮体介导的2-氧代戊二酸脱氢酶抑制是由于线粒体内CoASH减少，并且这种对柠檬酸循环的抑制是伴随收缩功能衰竭的一种合理机制。
