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.

Highlights

  • Barth syndrome is a complex metabolic disorder caused by mutations in the mitochondrial transacylase tafazzin

  • Deconvolution of the biophysical, temporal, and integrated roles of cardiolipin, its metabolic intermediates (MLCL and DLCL), as well as the integrated processes by which cardiolipin is remodeled represents a paramount goal to understanding the mechanisms by which the mitochondrial membrane regulates bioenergetic homeostasis [57]

  • The results of the present study investigating cardiac bioenergetic, lipidomic, and signaling mechanisms in the Taz tafazzin shRNA knockdown (KD) mouse model of Barth syndrome demonstrate: i) clear resemblance of the mouse model to the human condition resulting in the accumulation of MLCL with the unexpected accumulation of DLCL; ii) altered distribution of acyl chains in choline and ethanolamine glycerophospholipids; iii) dysregulated generation of potent oxidized lipid metabolites critical for hemodynamic function; iv) a shift in preference for glutamate-stimulated oxidation; and v) an inability of the regulation of cardiolipin synthetic or mitochondrial phospholipase activities to attenuate altered cardiolipin remodeling in the tafazzin shRNA Barth syndrome mouse model

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Summary

Introduction

Barth syndrome is a complex metabolic disorder caused by mutations in the mitochondrial transacylase tafazzin. 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. 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.—Kiebish, M. The pleiotropic roles of tafazzin and cardiolipin (as well as its downstream sequelae) in regulating cellular signaling through modulation of metabolic efficiency, membrane dynamics, and multiple other mitochondrial functions have remained enigmatic [9]. The precisely regulated balance of cardiolipin synthesis, remodeling, and degradation exerts tight regulatory control of mitochondrial membrane structure and function

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