Characterization of critical differences between human and parasite respiratory complex II

几乎所有真核细胞的生存都依赖于线粒体，细胞的能量制造室。这对于人体细胞和引起弓形体病或疟疾等疾病的单细胞寄生虫来说都是如此。在线粒体中，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。电子的这种传输为通路提供动力，反过来使细胞存活和功能所需的构建模块和能量。出于这个原因，这条链中机器的抑制剂是致命的，而对寄生虫机器而不是人类机器具有特异性的分子可以成为优秀的药物。这方面的一个主要例子是临床使用的抗疟疾药物阿托伐醌，它抑制了这些机器之一。复合物II是链中的第二台机器，它完成了将电子带入链的关键作用。在人类中，复合物II由四种成分组成，它们共同形成从线粒体获得电子并将它们沿着链向前转移的部分。在顶复门（apicomplexans）中，导致弓形虫病、疟疾和其他疾病的寄生虫，复合物II的两个组分缺失，因此不清楚电子是如何向前传输的。这很奇怪，因为在所研究的任何其他生物体中，没有已知的功能复合物II缺失这些亚基。该项目旨在了解哪些独特的寄生虫因子能够实现这种基本复合物的功能，从而扩大我们对不同真核生物中这种基本细胞生物学过程的理解。顶复门寄生虫引起的疾病影响了全世界数百万人的健康。例如，疟疾每年感染超过200万人，造成约40万人死亡，主要影响非洲的儿童。弓形虫病是一种广泛的感染，发生在约1/3的世界人口中，一些国家，例如巴西，在人口中有>80%的感染。弓形虫病在免疫功能低下的患者中是致命的，并可导致新生儿缺陷和死胎。治疗顶复体的药物并不理想。抗药性是消灭疟疾的一个障碍，严重的副作用阻碍了弓形虫病的治疗。缺失的复合物II组分突出了寄生虫和人类细胞之间的根本差异，这可能代表了药物发现的机会。这一潜力由于该链已经是药物的已知靶点而得到增强。为了探索这种潜力，该领域需要知道什么成分构成了寄生虫复合体II，以及它们如何协同工作以执行其在链中的作用。因此，本项目的目标是1。识别组成寄生虫复合体II 2的成分。发现寄生虫生存所必需的所有组件3。阐明寄生虫与人类复合物II功能机制的差异。总之，这些发现将揭示不同细胞之间的差异，并可能有助于未来针对致命的顶复门病原体设计新药。

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.