Abberant cardiolipin dynamics in Barth Syndrome

 描述（申请人提供）：线粒体是真核生物所必需的富含膜的细胞器。线粒体膜蛋白的组装和动力学已经有了详细的了解，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。Barth综合征（BTHS）是脂质的线粒体代谢障碍，特别是线粒体特异性脂质心磷脂，因此提供了在与人类健康相关的背景下解决该缺口的独特机会。本申请的目的是确定导致BTHS中心磷脂被溶血心磷脂部分替代的机制，并阐明其功能后果。这一目标符合我们的广泛目标，了解心磷脂在线粒体中的功能，并解开BTHS的分子病理生理学。BTHS是由脂质酰基转移酶tafazzin的突变引起的，其导致先天性心肌病，其中心肌的正常分化受损。基于我们的初步数据，我们假设BTHS中的心肌病是由心磷脂的持续降解引起的，心磷脂的持续降解降低了心磷脂水平，并干扰了无定形干细胞线粒体向富含嵴的心肌细胞线粒体的发育。为了研究这一假设，我们提出（i）确定tafazzin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）确定心磷脂降解的抑制是否改善心脏线粒体的功能。具体来说，我们将确定周转率的增加是否是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的， 催化心磷脂降解的磷脂酶。在tafazzin敲低的小鼠模型中，我们将确定心磷脂是关键的胚胎学阶段，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），已知它们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的降解，以确定它们是否可以改善tafazzin敲除小鼠的心脏功能。这项研究意义重大，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。这些结果将通过绘制从祖细胞中的早期线粒体到心肌细胞中分化的线粒体的转变，填补我们对线粒体在心脏胚胎发育中的作用的知识中的一个关键空白。

 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.