Mapping the Human Platelet Lipidome Reveals Cytosolic Phospholipase A2 as a Regulator of Mitochondrial Bioenergetics during Activation.
Mapping the Human Platelet Lipidome Reveals Cytosolic Phospholipase A2 as a Regulator of Mitochondrial Bioenergetics during Activation.
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DOI：
10.1016/j.cmet.2016.04.001
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发表时间：
2016-05-10
期刊：
影响因子：
29
通讯作者：
O'Donnell VB
中科院分区：
文献类型：
--
作者：
Slatter DA;Aldrovandi M;O'Connor A;Allen SM;Brasher CJ;Murphy RC;Mecklemann S;Ravi S;Darley-Usmar V;O'Donnell VB
人的血小板在刺激后显著增加线粒体的能量产生。在这里，发现了一个脂体回路，其中底物是唯一由cPLA2提供的，包括支持通过β氧化产生能量的多种脂肪酸和被氧化的物种。这表明，在血小板激活过程中，需要急性脂膜重塑来支持能量需求。磷脂酶活性与能量代谢有关，表明cPLA2是脂质组学和能量流的中心调节因子。使用脂质组学方法(LipidArray)，我们还估计了静息、凝血酶激活和阿司匹林化的血小板中的脂质总数。遗传无关的个体和丰富的物种之间的显著多样性被揭示出来。静息血小板显示了∼5,600个独特的物种，推测只有50%的∼被鉴定出来。凝血酶使∼900脂类增加2倍，其中86%是新出现的，45%是阿司匹林补充剂抑制的，表明COX-1是主要激活依赖的脂类流动所必需的。从结构上鉴定了多种脂类。由于数据库中没有∼50%的脂类，这为挖掘与人类健康和疾病相关的脂类提供了一个重大机会。提供了静息和激动剂激活的人血小板的完整脂质体。补充小剂量阿司匹林深刻影响了三个无关个体的脂质体的显着差异。胞浆磷脂酶A2为线粒体耗氧提供脂质。描述人类血小板的脂质体网络。除了近200种氧化物种的特征外，该来源还表明，通过磷脂酶活性重塑细胞膜为呼吸提供了能量底物。这些发现证明了先天免疫和人类血小板线粒体生物能量学之间的直接联系。
Human platelets acutely increase mitochondrial energy generation following stimulation. Herein, a lipidomic circuit was uncovered whereby the substrates for this are exclusively provided by cPLA2, including multiple fatty acids and oxidized species that support energy generation via β-oxidation. This indicates that acute lipid membrane remodeling is required to support energetic demands during platelet activation. Phospholipase activity is linked to energy metabolism, revealing cPLA2 as a central regulator of both lipidomics and energy flux. Using a lipidomic approach (LipidArrays), we also estimated the total number of lipids in resting, thrombin-activated, and aspirinized platelets. Significant diversity between genetically unrelated individuals and a wealth of species was revealed. Resting platelets demonstrated ∼5,600 unique species, with only ∼50% being putatively identified. Thrombin elevated ∼900 lipids >2-fold with 86% newly appearing and 45% inhibited by aspirin supplementation, indicating COX-1 is required for major activation-dependent lipidomic fluxes. Many lipids were structurally identified. With ∼50% of the lipids being absent from databases, a major opportunity for mining lipids relevant to human health and disease is presented. The complete lipidome of resting and agonist-activated human platelets is presented Low-dose aspirin supplementation profoundly affects the platelet lipidome Significant diversity in the lipidomes of three unrelated individuals is seen Cytosolic phospholipase A2 provides lipids for mitochondrial oxygen consumption Slatter et al. characterize the lipidomic network of human platelets. Besides the characterization of nearly 200 oxidized species, the resource shows that remodeling of the membrane via phospholipase activity provides energy substrates for respiration. The findings demonstrate a direct link between innate immunity and mitochondrial bioenergetics in human platelets.