title: Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome.
abstract: Barth syndrome is a complex metabolic disorder caused by mutations in the mitochondrial transacylase tafazzin. Recently, an inducible tafazzin shRNA knockdown mouse model was generated to deconvolute the complex bioenergetic phenotype of this disease. To investigate the underlying cause of hemodynamic dysfunction in Barth syndrome, we interrogated the cardiac structural and signaling lipidome of this mouse model as well as its myocardial bioenergetic phenotype. A decrease in the distribution of cardiolipin molecular species and robust increases in monolysocardiolipin and dilysocardiolipin were demonstrated. Additionally, the contents of choline and ethanolamine glycerophospholipid molecular species containing precursors for lipid signaling at the sn-2 position were altered. Lipidomic analyses revealed specific dysregulation of HETEs and prostanoids, as well as oxidized linoleic and docosahexaenoic metabolites. Bioenergetic interrogation uncovered differential substrate utilization as well as decreases in Complex III and V activities. Transgenic expression of cardiolipin synthase or iPLA2γ ablation in tafazzin-deficient mice did not rescue the observed phenotype. These results underscore the complex nature of alterations in cardiolipin metabolism mediated by tafazzin loss of function. Collectively, we identified specific lipidomic, bioenergetic, and signaling alterations in a murine model that parallel those of Barth syndrome thereby providing novel insights into the pathophysiology of this debilitating disease.
authors: Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and.
authors: Michael A
authors: MA
authors: Kiebish
authors: Kui
authors: K
authors: Yang
authors: Xinping
authors: X
authors: Liu
authors: David J
authors: DJ
authors: Mancuso
authors: Shaoping
authors: S
authors: Guan
authors: Zhongdan
authors: Z
authors: Zhao
authors: Harold F
authors: HF
authors: Sims
authors: Rebekah
authors: R
authors: Cerqua
authors: W Todd
authors: WT
authors: Cade
authors: Xianlin
authors: X
authors: Han
authors: Richard W
authors: RW
authors: Gross
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D056889:Barth Syndrome / Q000378:metabolism* / Q000473:pathology; D002308:Cardiolipins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism; D015398:Signal Transduction; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D008055:Lipids; D008565:Membrane Proteins; D017855:Transferases (Other Substituted Phosphate Groups); C100091:cardiolipin synthetase