Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome
Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome
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DOI：
10.1194/jlr.m034728
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发表时间：
2013-05-01
影响因子：
6.5
通讯作者：
Gross, Richard W.
中科院分区：
文献类型：
--
作者：
Kiebish, Michael A.;Yang, Kui;Gross, Richard W.
巴特综合征是一种复杂的代谢性疾病，由线粒体转酰基酶他法津突变引起。最近，建立了一种可诱导的Tafazzin shRNA敲除小鼠模型来解开这种疾病的复杂的生物能量表型。为了探讨Barth综合征血流动力学障碍的根本原因，我们询问了这种小鼠模型的心脏结构和信号脂体以及它的心肌生物能量表型。心磷脂分子种类的分布减少，而单溶心磷脂和双溶心磷脂的分布明显增加。此外，sn-2位含有脂质信号前体的胆碱和乙醇胺甘油磷脂分子种类的含量也发生了变化。脂组学分析显示HETES和前列腺素类物质以及氧化的亚油酸和二十二碳六烯酸代谢物的特殊失调。生物能量分析发现底物利用的差异以及复合体III和V活性的降低。在他法津缺乏的小鼠中，转基因表达心磷脂合成酶或iPLA2(2)伽玛消融并不能挽救观察到的表型。这些结果强调了由他法津功能丧失引起的心磷脂代谢改变的复杂性。总的来说，我们在与Barth综合征相似的小鼠模型中发现了特定的脂体、生物能量和信号变化，从而为这种令人衰弱的疾病的病理生理学提供了新的见解。-Kiebish，M.A.，K.Yang，X.Liu，D.J.Mancuso，S.Guan，Z.赵，H.F.Sims，R.Cerqua，W.T.Cade，X.han和R.W.Gross。Barth综合征小鼠模型心肌线粒体功能障碍的生物能量、脂类和信号传递。J.Lipid Res.2013年。54：1312-第1325。
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)gamma 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.-Kiebish, M. A., K. Yang, X. Liu, D. J. Mancuso, S. Guan, Z. Zhao, H. F. Sims, R. Cerqua, W. T. Cade, X. Han, and R. W. Gross. Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome. J. Lipid Res. 2013. 54: 1312-1325.