Platelet mitochondrial function in health and disease

项目摘要/摘要 随着肥胖症在美国的流行，糖尿病日益引起人们的关注。糖尿病患者最多 患者将死于血栓性血管事件(心脏病发作或中风)，其中氧化的影响 由高血糖等主要代谢紊乱引起的对血小板的应激起着主要作用。 氧化应激是如何直接导致血小板功能障碍的，目前是一个热门的研究领域。我们 最近对糖尿病患者和健康患者的血小板进行了严格的蛋白质组和代谢组学分析 并确定了关键线粒体代谢蛋白中特定的氧化蛋氨酸修饰，这可能 是一些主要细胞代谢紊乱的根源(有丝分裂缺陷和脂质β- 氧化)与糖尿病血小板有关。此外，MsrB2，一种未被研究的线粒体基质 酶，可以逆转这些氧化应激诱导的蛋氨酸氧化变化，保护血小板。 根据我们的初步研究，我们假设糖尿病相关的氧化应激改变关键 参与基本细胞生物学和生化过程的蛋白质；线粒体特有的MsrB2 可能在逆转这种潜在的有害变化方面发挥关键作用，从而保护糖尿病患者免受 血栓事件。在解释我们的假设时，我们提出了三个具体目标。具体目标#1将 以评估氧化应激对帕金和最近描述的血小板有丝分裂的影响 保护过程。具体目标2将是确定蛋氨酸修饰HADHA是否是一个关键 线粒体三功能蛋白的组成部分，干扰线粒体的β-氧化。第三 具体目标是解决除了可能之外，MsrB2是否在纠正这些干扰方面发挥作用 治疗的其他抗氧化剂途径。我们的国际公认的专家团队在以下领域 糖尿病、血小板生物学、线粒体生物学和新陈代谢将在短期内破译 糖尿病中调控线粒体功能障碍和细胞凋亡的重要新机制。在 从长远来看，我们将为治疗血小板介导的不良反应确定新的靶点。 糖尿病的心血管事件。

PROJECT SUMMARY/ABSTRACT With the increasing prevalence of obesity in the USA, diabetes mellitus is a growing concern. Most diabetic patients will die from a thrombotic vascular event (heart attack or stroke) where the effects of oxidative stress on platelets, arising from major metabolic disturbances such has hyperglycemia, play a major role. How oxidative stress directly leads to platelet dysfunction is currently an intense area of investigation. We have recently performed rigorous proteomic and metabolomic profiling in diabetic versus healthy platelets and identified specific oxidized methionine modifications in key mitochondrial metabolic proteins, that may be the source for some of the major cellular metabolic disturbances (defects in mitophagy and lipid beta- oxidation) associated with diabetic platelets. Moreover, MsrB2, an understudied mitochondrial matrix enzyme, can reverse these oxidative-stress induced methionine oxidative changes, protecting platelets. Based upon our Preliminary Studies we hypothesize that DM associated oxidative stress modifies key proteins involved in essential cellular biological and biochemical processes; mitochondria specific MsrB2 may play a critical role in reversing such potentially harmful changes, thus protecting DM patients from thrombovascular events. In addressing our hypothesis, we present three Specific Aims. Specific Aim #1 will be to assess the effects of oxidative stress on Parkin and the recently described platelet mitophagy protective process. Specific Aim #2 will be to determine whether methionine modification of HADHA, a key component of the mitochondrial trifunctional protein, perturbs mitochondrial beta-oxidation. The third Specific Aim addresses whether MsrB2 plays a role in rectifying these disturbances, in addition to possible other anti-oxidant avenues for therapy. Our team of internationally recognized experts in the areas of diabetes mellitus, platelet biology, mitochondrial biology and metabolism, will in the short term decipher important new mechanisms regulating mitochondrial dysfunction and apoptosis in diabetes mellitus. In the long term, we will have identified new targets for novel therapy against platelet mediated adverse cardiovascular events in diabetes mellitus.