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，影响全世界数百万人的健康， 仅在美国，每年的医疗费用至少为24亿美元。1它是由β -珠蛋白基因突变引起的 这导致血红蛋白S（HbS）的形成。HbS能够使红细胞镰状化，溶血， 急性和慢性疼痛，慢性溶血性贫血，多系统器官损伤，以及大大缩短的寿命 期待新的靶向治疗方法对于克服开始的事件级联至关重要 HbS聚合。最近，许多研究者已经证明SCD器官病理学与 氧化应激。氧化应激发生在氧化剂增加而没有类似的 抗氧化剂过量的ROS积累会引发一系列氧化反应，破坏脂质、蛋白质和 红细胞最终导致溶血或早期破坏。虽然ROS已经取得了很大的进展， 在SCD患者中，ROS介导的并发症，进一步的研究是必要的，试图了解ROS的来源 以及参与HbS聚合和溶血过程的因素。我们已经在实验室里证明， SCD RBC保留线粒体。此外，我们已经表明，这些保留的线粒体产生过量的 细胞内ROS的产生，并与溶血有关。我们的初步数据还显示， 线粒体引起红细胞中氧消耗增加。我们假设红细胞 线粒体滞留通过两种非相互排斥的方式导致SCD发病机制的恶化 机制1）线粒体产生过量的ROS，导致溶血和2）线粒体增加 氧消耗导致缺氧的细胞内环境，引起Hb S聚合。一个 理解线粒体氧消耗和随后的氧化应激在SCD发病机制中的作用 代表了靶向治疗剂开发的新机会。线粒体的可能性- RBC中衍生的ROS产生和氧消耗是以前没有研究过的新靶点。 我们的长期目标是将新发现的保留血小板的SCD RBC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.