Cardiolipin-mediated procoagulant activity of mitochondria contributes to traumatic brain injury-associated coagulopathy in mice.
Cardiolipin-mediated procoagulant activity of mitochondria contributes to traumatic brain injury-associated coagulopathy in mice.
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DOI：
10.1182/blood-2015-12-688838
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发表时间：
2016-06
期刊：
影响因子：
20.3
通讯作者：
Zilong Zhao;Min Wang;Ye Tian;Tristan Hilton;Breia J. Salsbery;E. Z. Zhou;Xiaoping Wu;P. Thiagarajan;É. Boilard;Min Li;Jian-ning Zhang;Jing-fei Dong
中科院分区：
文献类型：
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作者：
Zilong Zhao;Min Wang;Ye Tian;Tristan Hilton;Breia J. Salsbery;E. Z. Zhou;Xiaoping Wu;P. Thiagarajan;É. Boilard;Min Li;Jian-ning Zhang;Jing-fei Dong
心磷脂（CL）是一种阴离子磷脂，仅位于线粒体内膜。它在血液中的存在表明线粒体损伤和从受损细胞中释放。在此，我们报告了CL暴露的脑源性线粒体微粒（mtMPs）的检测在17 547 ± 2677/μL的小鼠遭受液压冲击脑损伤的外周血中。这些mtMP占损伤急性期所有血浆膜联蛋白V结合微粒的55.2% ± 12.6%。它们也从经历凋亡的培养的神经元和神经胶质细胞中释放。mtMP与血小板协同作用，通过破坏内皮屏障促进血管渗漏。破坏的内皮屏障允许mtMP释放到体循环中，以促进创伤性损伤和mtMP或CL注射小鼠的凝血，导致增强的纤维蛋白溶解、血管纤维蛋白沉积和血栓形成。这种线粒体膜蛋白诱导的凝血是由CL介导的，CL从线粒体内膜转运到线粒体外膜，并被清除分子lactadherin阻断。与线粒体膜蛋白结合的CL的促凝活性是纯化CL的1600倍。这项研究发现了一种新的促凝血活性的CL和CL暴露的线粒体，可能有助于创伤性脑损伤相关的凝血功能障碍，并确定了潜在的途径，以阻止这种活动。
Cardiolipin (CL) is an anionic phospholipid located exclusively in the mitochondrial inner membrane. Its presence in blood indicates mitochondrial damage and release from injured cells. Here, we report the detection of CL-exposed brain-derived mitochondrial microparticles (mtMPs) at 17 547 ± 2677/μL in the peripheral blood of mice subjected to fluid percussion injury to the brain. These mtMPs accounted for 55.2% ± 12.6% of all plasma annexin V-binding microparticles found in the acute phase of injury. They were also released from cultured neuronal and glial cells undergoing apoptosis. The mtMPs synergized with platelets to facilitate vascular leakage by disrupting the endothelial barrier. The disrupted endothelial barrier allowed the release of mtMPs into the systemic circulation to promote coagulation in both traumatically injured and mtMP- or CL-injected mice, leading to enhanced fibrinolysis, vascular fibrin deposition, and thrombosis. This mtMP-induced coagulation was mediated by CL transported from the inner to the outer mitochondrial membrane and was blocked by the scavenging molecule lactadherin. The mtMP-bound CL was ∼1600 times as active as purified CL in promoting coagulation. This study uncovered a novel procoagulant activity of CL and CL-exposed mitochondria that may contribute to traumatic brain injury-associated coagulopathy and identified potential pathways to block this activity.