Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction
Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction
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DOI：
10.1021/bi051908a
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发表时间：
2005-12-20
期刊：
影响因子：
2.9
通讯作者：
Gross, RW
中科院分区：
文献类型：
--
作者：
Han, XL;Yang, JY;Gross, RW
糖尿病性心肌病的特征是脂肪酸底物的过度利用、葡萄糖转运减少和线粒体功能障碍。然而，化学机制连接改变底物利用线粒体功能障碍是未知的。在此，我们使用鸟枪脂质组学和多维质谱来鉴定糖尿病小鼠心肌中关键的线粒体内膜脂质心磷脂的显著降低（从对照心脏中的7.2 +/-0.3nmol/mg蛋白质到糖尿病心肌中的3.1 +/-0.1nmol/mg蛋白质; p < 0.001，n = 7）。此外，心磷脂的直接代谢前体磷脂酰甘油也基本耗尽（对照心脏中2.5 +/-0.2nmol/ mg蛋白质vs糖尿病心肌中1.3 +/-0.1nmol/mg蛋白质; p < 0.001，n = 7）。类似地，磷脂酰甘油生产中倒数第二步所必需的甘油3-磷酸在糖尿病心肌中降低了58%（从4.9 +/- 0.9至2.2 +/- 0.3 nmol/mg蛋白; n = 4）。由于Barth综合征（心磷脂代谢紊乱）诱导线粒体功能障碍和心肌病，并由于心磷脂含量的减少沉淀线粒体功能障碍，这些结果提供了一个统一的假设连接改变底物利用和代谢流量与脂质代谢改变，心磷脂消耗，线粒体功能障碍，并由此产生的血流动力学妥协糖尿病心肌。
Diabetic cardiomyopathy is characterized by excessive utilization of fatty acid substrate, diminished glucose transport, and mitochondrial dysfunction. However, the chemical mechanisms linking altered substrate utilization to mitochondrial dysfunction are unknown. Herein, we use shotgun lipidomics and multidimensional mass spectrometry to identify dramatic decreases in the critical mitochondrial inner membrane lipid, cardiolipin, in diabetic murine myocardium (from 7.2 +/- 0.3 nmol/mg of protein in control hearts to 3.1 +/- 0.1 nmol/mg of protein in diabetic myocardium; p < 0.001, n = 7). Moreover, the direct metabolic precursor of cardiolipin, phosphatidylglycerol, was also substantially depleted (2.5 +/- 0.2 nmol/ mg of protein in control hearts vs 1.3 +/- 0.1 nmol/mg of protein in diabetic myocardium; p < 0.001, n = 7). Similarly, glycerol 3-phosphate, necessary for the penultimate step in phosphatidyl glycerol production, decreased by 58% in diabetic myocardium (from 4.9 +/- 0.9 to 2.2 +/- 0.3 nmol/mg of protein; n = 4). Since Barth's syndrome (a disorder of cardiolipin metabolism) induces mitochondrial dysfunction and cardiomyopathy, and since decreases in cardiolipin content precipitate mitochondrial dysfunction, these results provide a unifying hypothesis linking altered substrate utilization and metabolic flux in diabetic myocardium with altered lipid metabolism, cardiolipin depletion, mitochondrial dysfunction, and resultant hemodynamic compromise.