title: Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction.
abstract: 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 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 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.
authors.affiliation: Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. xianlin@wustl.edu
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.forename: Jingyue
authors.initials: J
authors.lastname: Yang
authors.forename: Hua
authors.initials: H
authors.lastname: Cheng
authors.forename: Kui
authors.initials: K
authors.lastname: Yang
authors.forename: Dana R
authors.initials: DR
authors.lastname: Abendschein
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002308:Cardiolipins / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005994:Glycerophosphates / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D010955:Plasmalogens / Q000378:metabolism; D012015:Reference Standards; D021241:Spectrometry, Mass, Electrospray Ionization; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D005994:Glycerophosphates; D008055:Lipids; D010955:Plasmalogens; D014280:Triglycerides; C020791:phosphatidal ethanolamines; C029620:alpha-glycerophosphoric acid