The Role of Erythrocyte Mitochondrial Retention in Sickle Cell Disease

镰状细胞病(SCD)是一种遗传性血液疾病，影响全球数百万人并导致健康 仅在美国，每年的医疗费用就至少达24亿美元。1这是由β-珠蛋白基因突变引起的 这导致了血红蛋白S(HBs)的形成。HBS能够聚合并导致红细胞皱缩，溶血， 急性和慢性疼痛、慢性溶血性贫血、多系统器官损伤以及寿命大大缩短 期望值。新的靶向治疗方法对于克服一连串开始的事件至关重要 与HBS聚合。最近，许多研究人员证明，SCD器官病理与 与氧化应激有关。当氧化剂增加而没有类似的增加时，就会发生氧化应激 抗氧化剂。过量的ROS积累触发了一连串的氧化反应，损害了脂质、蛋白质和 红细胞最终导致溶血或早期破坏。尽管ROS已经取得了很大的进展 SCD患者的介导性并发症，进一步的研究对于试图了解ROS的来源是必要的 以及影响HBS聚合和溶血过程的因素。我们已经在实验室里证明了 SCD红细胞保留线粒体。此外，我们已经证明，这些保留的线粒体会产生过量的 细胞内ROS的产生，与溶血有关。我们的初步数据还显示，这些 线粒体导致红细胞耗氧量增加。我们假设红血球 线粒体滞留通过两种非互斥机制加重SCD的发病 机制1)线粒体产生过量的ROS，导致溶血；2)线粒体增加 氧气消耗导致细胞内低氧环境，导致Hb S聚合。一个 对线粒体耗氧和氧化应激在SCD发病机制中的认识 为靶向治疗剂的发展提供了一个新的机会。线粒体的可能性- 红细胞中衍生的ROS的产生和耗氧是以前从未被研究过的新靶标。 我们的长期目标是将保留线粒体的SCD红细胞的新发现转化为新的药物 镰状细胞病的治疗方法。

Sickle cell disease (SCD) is an inherited blood disorder that affects millions of people worldwide and results in health care costs of at least $2.4 billion per year in the United States alone.1 It is caused by a mutation in the β -globin gene which leads to the formation of hemoglobin S (HbS). HbS is able to polymerize and leads to RBC sickling, hemolysis, acute and chronic pain, chronic hemolytic anemia, multisystem organ damage, and a much-shortened life expectancy. Novel targeted therapeutic approaches are essential to overcome the cascade of the events that begin with HbS polymerization. Recently many investigators have demonstrated that SCD organ pathology is associated with oxidative stress. Oxidative stress occurs when there is an increase in oxidants without a similar increase in antioxidants. Excessive ROS accumulation triggers a cascade of oxidative reactions that damage lipids, proteins of red blood cells ultimately leading to hemolysis or early destruction. Although much progress has been made to ROS mediated complications in SCD patients, further studies are essential in an attempt to understand the source of ROS and factors involved in HbS polymerization and hemolytic process. We have demonstrated in our laboratory that SCD RBCs retain mitochondria. In addition, we have shown that these retained mitochondria create excessive intracellular ROS generation and are associated with hemolysis. Our preliminary data also show that these mitochondria cause an increased oxygen consumption in the red blood cells. We hypothesize that erythrocyte mitochondrial retention causes exacerbation of SCD pathogenesis by two non-mutually exclusive mechanisms 1) Mitochondria generate excessive ROS leading to hemolysis and 2) Mitochondria increased oxygen consumption leading to a hypoxic intracellular environment that causes Hb S polymerization. An understanding of mitochondrial oxygen consumption and consequential oxidative stress in the pathogenesis of SCD represents a novel opportunity for the development of targeted therapeutic agents. The possibility of mitochondria- derived ROS generation and oxygen consumption in RBCs are novel targets that have not been investigated before. Our long-term goal is to translate the novel finding of mitochondria-retaining SCD RBCs into new pharmaceutical therapies for sickle cell disease.