Wellcome Centre for Integrative Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow G12 8TA, UK.
Int J Mol Sci. 2024 Aug 26;25(17):9239. doi: 10.3390/ijms25179239.
The mitochondrial electron transport chain (mETC) is responsible for essential metabolic pathways such as de novo pyrimidine synthesis and ATP synthesis. The mETC complex III (cytochrome complex) is responsible for transferring electrons from ubiquinol to cytochrome and generating a proton gradient across the inner mitochondrial membrane, which is necessary for the function of ATP synthase. Recent studies have revealed that the composition of complex III (PfCIII) is divergent from humans, highlighting its suitability as a target for specific inhibition. Indeed, PfCIII is the target of the clinically used anti-malarial atovaquone and of several inhibitors undergoing pre-clinical trials, yet its role in parasite biology has not been thoroughly studied. We provide evidence that the universally conserved subunit, PfRieske, and the new parasite subunit, PfC3AP2, are part of PfCIII, with the latter providing support for the prediction of its divergent composition. Using inducible depletion, we show that PfRieske, and therefore, PfCIII as a whole, is essential for asexual blood stage parasite survival, in line with previous observations. We further found that depletion of PfRieske results in gametocyte maturation defects. These phenotypes are linked to defects in mitochondrial functions upon PfRieske depletion, including increased sensitivity to mETC inhibitors in asexual stages and decreased cristae abundance alongside abnormal mitochondrial morphology in gametocytes. This is the first study that explores the direct role of the PfCIII in gametogenesis via genetic disruption, paving the way for a better understanding of the role of mETC in the complex life cycle of these important parasites and providing further support for the focus of antimalarial drug development on this pathway.
线粒体电子传递链（mETC）负责重要的代谢途径，如从头嘧啶合成和 ATP 合成。mETC 复合物 III（细胞色素复合物）负责将电子从泛醇转移到细胞色素，并在内膜产生质子梯度，这是 ATP 合酶功能所必需的。最近的研究表明，复合物 III（PfCIII）的组成与人类不同，这突出了其作为特定抑制靶标的适用性。事实上，PfCIII 是临床上使用的抗疟药阿托伐醌和几种正在进行临床前试验的抑制剂的靶标，但它在寄生虫生物学中的作用尚未得到彻底研究。我们提供的证据表明，普遍保守的亚基 PfRieske 和新的寄生虫亚基 PfC3AP2 是 PfCIII 的一部分，后者支持了其组成差异的预测。通过诱导性耗尽，我们表明 PfRieske，因此，PfCIII 作为一个整体，对无性血期寄生虫的生存是必不可少的，这与之前的观察结果一致。我们还发现 PfRieske 的耗竭导致配子体成熟缺陷。这些表型与 PfRieske 耗尽后线粒体功能缺陷有关，包括在无性阶段对 mETC 抑制剂的敏感性增加，以及配子体中线粒体嵴丰度降低和形态异常。这是第一项通过遗传干扰探索 PfCIII 在配子发生中的直接作用的研究，为更好地理解 mETC 在这些重要寄生虫复杂生命周期中的作用铺平了道路，并为将抗疟药物开发的重点放在该途径上提供了进一步支持。
