Abberant cardiolipin dynamics in Barth Syndrome

巴特综合征中心磷脂动力学异常

基本信息

批准号：
8940820
负责人：
Michael Schlame
金额：
$ 40.68万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/8940820
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 Embryonic Development Enzymes Fatty Acids Functional disorder Goals Half-Life Health Heart Homeostasis Human Knowledge Laboratories Life Link Lipids Lysophospholipids Maintenance Maps Mass Spectrum Analysis Measures Membrane Membrane Potentials Mission Mitochondria Mitochondrial Diseases Mitochondrial Membrane Protein Molecular Morphology Mus Mutation Myocardium Organelles Pathogenesis Pattern Perinatal Pharmaceutical Preparations Phase Phospholipase Phospholipids Public Health Research Resveratrol Role Specificity Stable Isotope Labeling Staging Stem cells Testing Transacylase Work base cardiogenesis disability improved improved functioning insight knock-down lipid metabolism mitochondrial dysfunction mitochondrial membrane mortality mouse model novel oxidation preference prenatal prevent progenitor public health relevance respiratory skeletal tool

项目摘要

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（由申请人提供）：线粒体是对真核生命至关重要的富含膜的细胞器，人们对线粒体膜蛋白的组装和动力学有了详细的了解，但在理解线粒体脂质的动力学方面仍然存在根本性的差距。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质心磷脂，因此为在与人类健康相关的背景下解决这一差距提供了独特的机会。该应用的目的是确定 BTHS 中心磷脂被单溶心磷脂部分替代的机制，并阐明其功能后果，这一目标符合我们了解心磷脂在线粒体中的功能和揭示 BTHS 分子病理生理学的广泛目标。 BTHS 是由脂质酰基转移酶 tafazzin 突变引起的，会导致先天性心肌病，导致心肌的正常分化受损。根据我们的初步数据，我们认为 BTHS 的心肌病是由心磷脂的持续降解引起的，这会降低心磷脂水平并扰乱无形状干细胞线粒体向富含嵴的心肌细胞线粒体的发育。 tafazzin 缺乏导致心磷脂降解的机制，(ii) 确定心磷脂消耗对心肌细胞分化的影响，以及 (iii) 确定抑制心磷脂降解是否可以改善心肌细胞分化具体来说，我们将确定周转增加是否是由心磷脂不饱和度降低、心磷脂氧化增加或心磷脂在膜内定位引起的，并且我们将确定在催化心磷脂降解的小鼠模型中，我们将确定心磷脂至关重要的胚胎阶段，并确定心磷脂缺失对心脏分化的影响。白藜芦醇和苯扎贝特）已知可以增加超复合物的组装，并且我们已经证明它们可以抑制心磷脂降解，以确定它们是否可以改善心脏功能这项研究具有重要意义，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，结果将弥补我们对线粒体在 BTHS 中的作用的认识上的一个关键空白。通过绘制祖细胞中早期线粒体到心肌细胞中分化线粒体的转变来研究心脏的胚胎发育。