Impaired energy metabolism of the taurine-deficient heart
Impaired energy metabolism of the taurine-deficient heart
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DOI：
10.1007/s00726-015-2110-2
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发表时间：
2016-02-01
期刊：
影响因子：
3.5
通讯作者：
Takahashi, Kyoko
中科院分区：
文献类型：
--
作者：
Schaffer, Stephen W.;Shimada-Takaura, Kayoko;Takahashi, Kyoko
牛磺酸是一种β-氨基酸，在包括心脏在内的兴奋性组织中含量很高。心肌牛磺酸含量的显著降低会导致一种独特的扩张型、萎缩性心肌病的发生。牛磺酸在心脏中的主要功能之一是调节呼吸链。因此，我们验证了牛磺酸缺乏导致呼吸链功能缺陷导致能量代谢受损和ATP生成减少的假设。我们发现，虽然牛磺酸缺乏的心脏的糖酵解速度显著增加，但葡萄糖的氧化作用减弱。葡萄糖氧化还原的主要部位是丙酮酸脱氢酶，该酶的活性随着NADH/NAD(+)比值的增加和丙酮酸氧化为乙酰辅酶A的有效性的降低以及[Mg2+](I)的变化而降低。在牛磺酸缺乏的心脏中，另外两种乙酰辅酶A前体--内源性脂肪酸和外源性醋酸酯的氧化也减少了。在牛磺酸缺乏的心脏中，柠檬酸循环活性受损减少了醋酸盐氧化和内源性脂肪酸氧化，但线粒体转运体肉碱棕榈酰转移酶活性的降低似乎也有助于减少脂肪酸氧化。这些变化降低了ATP的产生速度，导致了磷酸肌酸/ATP比率的下降，这是能量状态下降的迹象。这些发现支持这样一种假设，即牛磺酸缺乏的心脏主要是由于呼吸链功能受损、NADH/NAD(+)比率增加以及线粒体摄取长链脂肪酸减少而导致能量匮乏。结果表明，改善能量代谢有助于牛磺酸治疗心力衰竭患者的有益效果。
Taurine is a beta-amino acid found in high concentrations in excitable tissues, including the heart. A significant reduction in myocardial taurine content leads to the development of a unique dilated, atrophic cardiomyopathy. One of the major functions of taurine in the heart is the regulation of the respiratory chain. Hence, we tested the hypothesis that taurine deficiency-mediated defects in respiratory chain function lead to impaired energy metabolism and reduced ATP generation. We found that while the rate of glycolysis was significantly enhanced in the taurine-deficient heart, glucose oxidation was diminished. The major site of reduced glucose oxidation was pyruvate dehydrogenase, an enzyme whose activity is reduced by the increase in the NADH/NAD(+) ratio and by decreased availability of pyruvate for oxidation to acetyl CoA and changes in [Mg2+](i). Also diminished in the taurine-deficient heart was the oxidation of two other precursors of acetyl CoA, endogenous fatty acids and exogenous acetate. In the taurine-deficient heart, impaired citric acid cycle activity decreased both acetate oxidation and endogenous fatty acid oxidation, but reductions in the activity of the mitochondrial transporter, carnitine palmitoyl transferase, appeared to also contribute to the reduction in fatty acid oxidation. These changes diminished the rate of ATP production, causing a decline in the phosphocreatine/ATP ratio, a sign of reduced energy status. The findings support the hypothesis that the taurine-deficient heart is energy starved primarily because of impaired respiratory chain function, an increase in the NADH/NAD(+) ratio and diminished long chain fatty acid uptake by the mitochondria. The results suggest that improved energy metabolism contributes to the beneficial effect of taurine therapy in patients suffering from heart failure.