Characterization of critical differences between human and parasite respiratory complex II

人类和寄生虫呼吸复合物 II 之间关键差异的表征

• 批准号: MR/W002221/1
• 负责人: Lilach Sheiner
• 金额: $ 47.15万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW002221%2F1
• 关键词: Characterization; critical; differences; between; human

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.

几乎所有真核细胞的生存都依赖于线粒体，这是细胞的能量制造单元。人体细胞和引起弓形虫病或疟疾等疾病的单细胞寄生虫也是如此。在线粒体中，一条名为电子传输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，而通路反过来又为细胞的生存和功能提供必要的积木和能量。出于这个原因，这一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具有特异性的分子可以制造出极好的药物。一个最好的例子是临床上使用的抗疟疾药物阿托瓦酮，它可以抑制其中一个机器。复合体II是链条上的第二台机器，它发挥着将电子带入链条的关键作用。在人类中，复合体II由四个组成部分组成，这四个组成部分共同形成了从线粒体获取电子并向下传递电子的部分。在顶端复合体中，导致弓形虫病、疟疾和其他疾病的一组寄生虫中，两个复杂的II成分缺失，因此尚不清楚电子是如何向前传输的。这很奇怪，因为在任何其他被研究的生物体中，都没有已知的功能复合体II缺失这些亚单位。本项目旨在了解是什么独特的寄生因子使这个重要的复合体发挥作用，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。Apicomplexan寄生虫引起的疾病影响着世界各地数百万人的健康。例如，疟疾每年感染200万人，导致约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，发生在世界三分之一的人口中，一些国家，例如巴西，人口中有80%的人感染。弓形虫病在免疫功能低下的患者中可能是致命的，并可能导致新生儿缺陷和死产。治疗顶端复合体的药物并不理想。耐药性是根除疟疾的障碍，严重的副作用阻碍了弓形虫病的治疗。缺失的复合体II组分突显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。该链已成为已知的药物靶标，这一事实加强了这种潜力。为了探索这一潜力，该领域需要知道哪些组件组成寄生虫复合体II，以及它们如何协同工作以执行其在链中的角色。因此，本项目的目标是1.确定构成寄生虫复合体的组件2。发现寄生虫生存所必需的所有成分3。阐明寄生虫和人类复合体II功能机制的差异。总而言之，这些发现将阐明分化细胞之间的差异，并可能有助于未来针对致命的顶端复合体病原体的新药设计。

项目成果

The mystery of massive mitochondrial complexes: the apicomplexan respiratory chain.

• DOI: 10.1016/j.pt.2022.09.008
• 发表时间: 2022-12
• 期刊: TRENDS IN PARASITOLOGY
• 影响因子: 9.6
• 作者: Maclean, Andrew E.;Hayward, Jenni A.;Huet, Diego;van Dooren, Giel G.;Sheiner, Lilach
• 通讯作者: Sheiner, Lilach