| Abstract
| - Diabetic cardiomyopathy is characterized by excessive utilization of fatty acid substrate,diminished glucose transport, and mitochondrial dysfunction. However, the chemical mechanisms linkingaltered substrate utilization to mitochondrial dysfunction are unknown. Herein, we use shotgun lipidomicsand multidimensional mass spectrometry to identify dramatic decreases in the critical mitochondrial innermembrane lipid, cardiolipin, in diabetic murine myocardium (from 7.2 ± 0.3 nmol/mg of protein in controlhearts to 3.1 ± 0.1 nmol/mg of protein in diabetic myocardium; p< 0.001, n = 7). Moreover, the directmetabolic 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 phosphatidylglycerol 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 andcardiomyopathy, and since decreases in cardiolipin content precipitate mitochondrial dysfunction, theseresults provide a unifying hypothesis linking altered substrate utilization and metabolic flux in diabeticmyocardium with altered lipid metabolism, cardiolipin depletion, mitochondrial dysfunction, and resultanthemodynamic compromise.
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