Mitochondrial fusion protein MFN2 prevents platelet death and dysfunction

摘要 线粒体功能障碍与许多疾病有关，包括血栓形成和 止血。血小板从巨核细胞继承了功能完整的线粒体，但巨核细胞是如何 线粒体在其独特的发育过程中保持完整性和功能尚不清楚。遗传 已有研究表明线粒体维持和融合蛋白Mfn2与血小板有关 罪名和心血管疾病。我们的初步数据显示，人类血小板中Mfn2的丢失是 与体外加速的血小板死亡有关。小鼠体内MNF2基因敲除降低了血小板存活率， 止血和血栓形成受损。初步数据显示线粒体的作用：Mfn2的丢失中断 巨核细胞线粒体形态改变，血小板线粒体功能受损。 在目标1中，我们检验了假设，即Mfn2在 巨核细胞发育，以确保血小板遗传完全功能和长寿的线粒体。在AIM 2 我们检验了这一假设，即Mfn2的缺失会导致血小板死亡、功能障碍和止血功能改变。 血栓形成。由于Mfn2在适应新陈代谢压力方面特别重要，我们将对它们逐一进行测试 在正常情况下和代谢应激期间的假设。每个目标都会有一只老鼠和一个人 组件：对于小鼠研究，我们将使用血小板/巨核细胞特异性Mfn2基因敲除，对于人类，将使用Mfn2基因敲除 研究中，我们将利用含有显著降低Mfn2表达的基因变体的原代细胞 血小板。 这项工作具有重要意义，因为其结果可能会导致针对血栓形成靶向障碍的新方法 止血，改善血小板的生成和储存。这项工作是创新的：我们将研究 线粒体融合--代谢过程中调节健康血小板存活和功能的新途径 压力，以及输注的血小板。我们将用创新的方法来检测新的线粒体功能 和循环老化的血小板。我们的研究将为Mfn2如何影响血小板死亡和 功能障碍，理解为什么人类Mfn2变异与血小板相关的重要一步 罪名和心血管疾病。

Abstract Mitochondrial dysfunction is associated with numerous diseases, including disorders of thrombosis and hemostasis. Platelets inherit fully functional mitochondria from megakaryocytes, yet how megakaryocytes maintain mitochondrial integrity and function during their unique developmental process is unknown. Genetic studies have associated the mitochondrial maintenance and fusion protein Mitofusin 2 (MFN2) with platelet counts and cardiovascular disease. Our preliminary data show that loss of MFN2 in human platelets is associated with accelerated platelet death in vitro. Knockout of MNF2 in mice reduced platelet survival, and impaired hemostasis and thrombosis. Preliminary data suggest a mitochondrial role: loss of MFN2 disrupted mitochondrial morphology in megakaryocytes, and impaired mitochondrial function in platelets. In Aim 1 we test the hypothesis that MFN2 maintains mitochondrial integrity and function during megakaryocyte development to ensure platelets inherit fully functional and long-lived mitochondria. In Aim 2 we test the hypothesis that loss of MFN2 leads to platelet death, dysfunction, and altered hemostasis and thrombosis. Because MFN2 is especially important in adapting to metabolic stress, we will test each of these hypotheses under normal conditions and during metabolic stress. Each aim will have a mouse and human component: for mouse studies we will use platelet/megakaryocyte specific MFN2 knockouts, and for human studies we will utilize primary cells harboring a genetic variant that significantly reduces MFN2 expression in platelets. This work is significant because the results may lead to new approaches to target disorders of thrombosis and hemostasis, and improve platelet production and storage. This work is innovative: we will examine mitochondrial fusion, a novel pathway regulating platelet survival and function in health, during metabolic stress, and in transfused platelets. We will use innovative methods to examine mitochondrial function in new and circulatory aged platelets. Our studies will provide new insights into how MFN2 affects platelet death and dysfunction, an important step into understanding why human MFN2 variants are associated with platelet counts and cardiovascular disease.