Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome

Michael A. Kiebish, Kui Yang, Xinping Liu, David J. Mancuso, Shaoping Guan, Zhongdan Zhao, Harold F. Sims, Rebekah Cerqua, W. Todd Cade, Xianlin Han, Richard W. Gross

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


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 iPLA 2 γ 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.

Original languageEnglish
Pages (from-to)1312-1325
Number of pages14
JournalJournal of lipid research
Issue number5
StatePublished - May 2013


  • Cardiolipin
  • Cardiolipin synthase
  • Electron transport chain
  • Lipidome
  • Mitochondria
  • Phospholipase
  • Tafazzin
  • Transgenic


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