Characterization of critical differences between human and parasite respiratory complex II

几乎所有真核细胞的存活都依赖于线粒体，这是细胞的能量制造室。这对人体细胞和引起弓形虫病或疟疾等疾病的单细胞寄生虫都是如此。在线粒体中，有一条被称为电子传递链的机器链，必须将线粒体内产生的电子传递给氧气。这种电子的传递为各种途径提供动力，反过来又为细胞的生存和功能提供必要的构件和能量。由于这个原因，这条链中机器的抑制剂是致命的，而对寄生虫机器比对人类机器有特异性的分子可以制成很好的药物。一个主要的例子是临床使用的抗疟疾药物阿托伐醌，它可以抑制这些机器中的一个。配合物II是链中的第二个机器，它完成了将电子带入链中的关键作用。在人类中，复合体II由四种成分组成，它们共同构成了从线粒体获取电子并将其转移到链上的部分。在顶复体虫（引起弓形虫病、疟疾和其他疾病的一类寄生虫）中，缺少两个复合物II组分，因此不清楚电子是如何向前传递的。这很奇怪，因为在研究的任何其他生物体中，都没有已知的功能复合体II缺少这些亚基。该项目旨在了解是什么独特的寄生虫因素使这一基本复合物发挥作用，从而扩大我们对不同真核生物中这一基本细胞生物学过程的理解。顶复合体寄生虫引起的疾病影响着全世界数百万人的健康。例如，疟疾每年感染200万人，导致40万人死亡，主要影响非洲的儿童。弓形虫病是一种广泛的传染病，发生在世界上约1/3的人口中，在一些国家，如巴西，人口感染率为80%。弓形虫病对免疫功能低下的患者可能是致命的，并可能导致新生儿缺陷和死胎。治疗顶复杂症的药物并不理想。耐药性是消灭疟疾的障碍，严重的副作用阻碍了弓形虫病的治疗。复合物II组分的缺失突出了寄生虫和人类细胞之间的根本区别，这可能代表着药物发现的机会。该链已经是已知的药物靶标，这一事实增强了这种潜力。为了探索这一潜力，该领域需要知道构成寄生虫复合体II的成分，以及它们如何协同工作以执行其在链中的作用。因此，这个项目的目标是1。确定构成寄生虫复合体II2的成分。发现寄生虫生存所必需的所有成分。阐明寄生虫与人复合物II功能机制的差异。总之，这些发现将阐明不同细胞之间的差异，并可能有助于未来设计针对致命的顶复合体病原体的新药。

The survival of almost any eukaryotic cell depends on the mitochondria, the cell's energy-making compartment. This is true for cells in the human body and for the single-celled parasites causing diseases like toxoplasmosis or malaria. In the mitochondria, a chain of machines, named the electron transport chain, must pass electrons, generated inside the mitochondria, to oxygen. This transport of electrons powers pathways that in return make building blocks and energy necessary for cell survival and function. For this reason, inhibitors of the machines in this chain are deadly, and molecules that have specificity for a parasite machine over a human one make excellent drugs. A prime example for this is the clinically used anti-malarial drug atovaquone, which inhibits one of these machines. Complex II, the second machine in the chain, fulfils the critical role of bringing electrons into the chain. In humans, complex II is made up of four components which together form the parts that acquire electrons from the mitochondria and that transfer them onwards down the chain. In apicomplexans, the group of parasites causing toxoplasmosis, malaria and other diseases, two of the complex II components are missing, and it is thus not clear how electrons are transported forward. This is curious because there is no known functional complex II missing those subunits in any other organism studied. This project aims to understand what unique parasite factors enable the function of this essential complex, thus, expanding our understanding of this fundamental cell biology process in divergent eukaryotes. Apicomplexan parasites cause diseases that affect the health of millions of people around the world. Malaria, for example, infects >2M and kills ~400,000 people a year, mainly affecting children in Africa. Toxoplasmosis is a widespread infection that occur in ~1/3 of the world's population, with some countries, for example Brazil, having >80% infection in the population. Toxoplasmosis can be fatal in immunocompromised patients, and can lead to defects in new-borns and stillbirth. Drugs for apicomplexans are suboptimal. Drug resistance is a barrier for malaria eradication and severe side effects hamper toxoplasmosis treatment. The missing complex II components highlight a fundamental difference between parasite and human cells, which may represent an opportunity for drug discovery. This potential is enhanced by the fact that the chain is already a known target for drugs. To explore this potential the field needs to know what components make up the parasites complex II, and how do they work together to execute its role in the chain. Therefore, the goals of this project are to 1. Identify the components that make up the parasite complex II2. Discover all the components that are essential for parasite survival3. Elucidate the differences in the mechanisms of parasite versus human complex II functions. Together these findings will shed light on the differences between divergent cells, and may assist the design of new drugs for the deadly apicomplexan pathogens in the future.