Abberant cardiolipin dynamics in Barth Syndrome

巴特综合征中心磷脂动力学异常

• 批准号: 9333386
• 负责人: Michael Schlame
• 金额: $ 35.12万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333386
• 关键词: 3-Methylglutaconic aciduria type 2; Acyltransferase; Address; Adult; Affect; Area; Bezafibrate; Bioenergetics; Biology; Cardiac; Cardiac Myocytes; Cardiolipins; Cardiomyopathies; Coupling; Crista ampullaris; Data; Development; Disease; Disease model; Embryonic Development; Enzymes; Fatty Acids; Functional disorder; Goals; Half-Life; Health; Heart; Homeostasis; Human; Impairment; Knowledge; Laboratories; Life; Link; Lipids; Lysophospholipids; Maintenance; Mass Spectrum Analysis; Measures; Membrane; Membrane Potentials; Metabolic Diseases; Mission; Mitochondria; Mitochondrial Diseases; Mitochondrial Membrane Protein; Molecular; Morphology; Mus; Mutation; Myocardium; Organelles; Pathogenesis; Pathogenicity; Pattern; Perinatal; Pharmaceutical Preparations; Phase; Phospholipase; Phospholipids; Public Health; Research; Resveratrol; Role; Specificity; Stable Isotope Labeling; Stem cells; Testing; Transacylase; United States National Institutes of Health; Work; base; cardiogenesis; disability; improved; improved functioning; insight; knock-down; lipid disorder; mitochondrial dysfunction; mitochondrial membrane; monolysocardiolipin; mortality; mouse model; novel; oxidation; preference; prenatal; prevent; progenitor; public health relevance; respiratory; skeletal; tool

 DESCRIPTION (provided by applicant): Mitochondria are membrane-rich organelles that are essential to eukaryotic life. Detailed insight has emerged into the assembly and the dynamics of mitochondrial membrane proteins, but a fundamental gap has remained in understanding the dynamics of mitochondrial lipids. Barth syndrome (BTHS) is a disorder of the mitochondrial metabolism of lipids, in particular the mitochondria-specific lipid cardiolipin, and thus provides unique opportunity to address this gap in a context relevant to human health. The objective of this application is to identify the mechanism that causes partial replacement of cardiolipin by monolyso-cardiolipin in BTHS and to elucidate its functional consequences. This objective fits into our broad goals to understand the function of cardiolipin in mitochondria and to unravel the molecular pathophysiology of BTHS. BTHS is caused by mutations in tafazzin, a lipid acyltransferase, which leads to an inborn cardiomyopathy, in which the normal differentiation of myocardium is impaired. Based on our preliminary data, we hypothesize that cardiomyopathy in BTHS results from continuous degradation of cardiolipin, which lowers cardiolipin levels and perturbs the development of shapeless stem cell mitochondria to cristae-rich cardiomyocyte mitochondria. To investigate this hypothesis, we propose (i) to identify the mechanism by which tafazzin deficiency causes cardiolipin degradation, (ii) to determine the effect of cardiolipin depletion on cardiomyocyte differentiation, and (iii) to establish whether inhibition of cardiolipi degradation improves the function of cardiac mitochondria. Specifically, we will determine whether the increased turnover is caused by decreased cardiolipin unsaturation, increased cardiolipin oxidation, or altered cardiolipin localization within the membrane and we will identify the phospholipase that catalyzes cardiolipin degradation. In a mouse model with tafazzin knock-down, we will determine the embryologic stage at which cardiolipin is critical and define the consequences that the loss of cardiolipin has for cardiac differentiation. Finally, we will test tw drugs (resveratrol and bezafibrate) that are known to increase supercomplex assembly and of which we have shown that they inhibit cardiolipin degradation, to determine whether they improve cardiac function in the tafazzin knockdown mouse. The proposed study is significant because it will establish the molecular pathogenesis of BTHS and it will test a potential therapy of the disease in a mouse model. The results will close a critical gap in our knowledge of the role of mitochondria in the embryologic development of the heart by mapping out the transition from early mitochondria in progenitor cells to differentiated mitochondria in cardiomyocytes.

 描述(申请人提供)：线粒体是富含细胞膜的细胞器，对真核生物来说是必不可少的。对线粒体膜蛋白的组装和动力学已经有了详细的见解，但在理解线粒体脂类的动力学方面仍然存在一个根本的差距。Barth综合征(BTHS)是一种脂质线粒体代谢紊乱，特别是线粒体特异性脂类心磷脂，因此在与人类健康相关的背景下提供了独特的机会来解决这一差距。本应用的目的是确定BTHS中单溶心磷脂部分替代心磷脂的机制，并阐明其功能后果。这一目标符合我们了解线粒体心磷脂功能和揭示BTHS分子病理生理学的广泛目标。BTHS是由脂酰基转移酶Tafazzin突变引起的，这种突变导致先天性心肌病，心肌的正常分化受到损害。根据我们的初步数据，我们假设BTHS的心肌病是由于心磷脂的持续降解导致的，心磷脂水平降低，并干扰了未成形的干细胞线粒体向富含冠状突的心肌细胞线粒体的发育。为了研究这一假说，我们建议(I)确定他法津缺乏导致心磷脂降解的机制，(Ii)确定心磷脂耗竭对心肌细胞分化的影响，以及(Iii)确定抑制心磷脂降解是否改善心肌线粒体的功能。具体地说，我们将确定周转率增加是否由心磷脂不饱和度降低、心磷脂氧化增加或膜内心磷脂定位改变引起，我们将确定 催化心磷脂降解的磷脂酶。在他法津基因敲除的小鼠模型中，我们将确定心磷脂发挥关键作用的胚胎学阶段，并确定心磷脂丢失对心脏分化的影响。最后，我们将测试两种药物(白藜芦醇和苯扎贝特)，这两种药物已知可以增加超复合体组装，并且我们已经证明它们抑制心磷脂降解，以确定它们是否改善了他法津基因敲除小鼠的心功能。这项拟议的研究具有重要意义，因为它将建立BTHS的分子发病机制，并将在小鼠模型中测试该疾病的潜在治疗方法。这一结果将通过绘制出从祖细胞中的早期线粒体到心肌细胞中分化的线粒体的过渡图，填补我们对线粒体在心脏胚胎发育中的作用的认识上的一个关键空白。