Schaffer Stephen W, Shimada-Takaura Kayoko, Jong Chian Ju, Ito Takashi, Takahashi Kyoko
Department of Pharmacology, University of South Alabama, College of Medicine, Mobile, AL 36688, USA.
Amino Acids. 2016 Feb;48(2):549-58. doi: 10.1007/s00726-015-2110-2.
Taurine is a β-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.
牛磺酸是一种β-氨基酸，在包括心脏在内的可兴奋组织中含量很高。心肌牛磺酸含量的显著降低会导致一种独特的扩张性、萎缩性心肌病的发展。牛磺酸在心脏中的主要功能之一是调节呼吸链。因此，我们检验了这样一个假设，即牛磺酸缺乏介导的呼吸链功能缺陷会导致能量代谢受损和ATP生成减少。我们发现，虽然在牛磺酸缺乏的心脏中糖酵解速率显著增强，但葡萄糖氧化却减少了。葡萄糖氧化减少的主要部位是丙酮酸脱氢酶，该酶的活性会因NADH/NAD⁺比值的增加、丙酮酸氧化为乙酰辅酶A的可用性降低以及细胞内镁离子浓度的变化而降低。在牛磺酸缺乏的心脏中，乙酰辅酶A的另外两种前体——内源性脂肪酸和外源性乙酸盐的氧化也减少了。在牛磺酸缺乏的心脏中，柠檬酸循环活性受损降低了乙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导致了脂肪酸氧化的减少。这些变化降低了ATP的产生速率，导致磷酸肌酸/ATP比值下降，这是能量状态降低的一个迹象。这些发现支持了这样一个假设，即牛磺酸缺乏的心脏主要因呼吸链功能受损、NADH/NAD⁺比值增加以及线粒体对长链脂肪酸摄取减少而处于能量饥饿状态。结果表明，改善能量代谢有助于牛磺酸治疗对心力衰竭患者的有益作用。
