Kiebish 2013 J Lipid Res

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Kiebish MA, Yang K, Liu X, Mancuso DJ, Guan S, Zhao Z, Sims HF, Cerqua R, Cade WT, Han X, Gross RW (2013) Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome. J Lipid Res 54:1312-25.

» PMID: 23410936 Open Access

Kiebish MA, Yang K, Liu X, Mancuso DJ, Guan S, Zhao Z, Sims HF, Cerqua R, Cade WT, Han X, Gross RW (2013) J Lipid Res

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, prostanoids, as well as oxidized linoleic and docosahexaenoic metabolites. Bioenergetic interrogation uncovered differential substrate utilization as well as deceases in Complex III and CV 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.

Keywords: Lipidome; Cardiolipin; Tafazzin; Phospholipase; Cardiolipin synthase; Barth syndrome

O2k-Network Lab: US MO St Louis Gross RW


Labels: MiParea: Respiration, nDNA;cell genetics, Genetic knockout;overexpression, mt-Medicine  Pathology: Other  Stress:Mitochondrial disease  Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: LEAK, OXPHOS  Pathway: F, N, S, NS  HRR: Oxygraph-2k