Malaria causes millions of deaths worldwide and is considered a huge burden to underdeveloped countries. The number of cases with resistance to all antimalarials is continuously increasing, making the identification of novel drugs a very urgent necessity. A potentially very interesting target for novel therapeutic intervention is the parasite mitochondrion. In this work, we studied in Plasmodium falciparum 3 genes coding for proteins homologues of the mammalian FIS1 (Mitochondrial Fission Protein 1) and DRP1 (Dynamin Related Protein 1) involved in mitochondrial fission. We studied the expression of P. falciparum genes that show ample sequence and structural homologies with the mammalian counterparts, namely FIS1, DYN1, and DYN2. The encoded proteins are characterized by a distinct pattern of expression throughout the erythrocytic cycle of P. falciparum, and their mRNAs are modulated by treating the parasite with the host hormone melatonin. We have previously reported that the knockout of the Plasmodium gene that codes for protein kinase 7 is essential for melatonin sensing. We here show that PfPk7 knockout results in major alterations of mitochondrial fission genes expression when compared to wild-type parasites, and no change in fission proteins expression upon treatment with the host hormone. Finally, we have compared the morphological characteristics (using MitoTracker Red CMX Ros) and oxygen consumption properties of P. falciparum mitochondria in wild-type parasites and PfPk7 Knockout strains. A novel GFP construct targeted to the mitochondrial matrix to wild-type parasites was also developed to visualize P. falciparum mitochondria. We here show that, the functional characteristics of P. falciparum are profoundly altered in cells lacking protein kinase 7, suggesting that this enzyme plays a major role in the control of mitochondrial morphogenesis and maturation during the intra-erythrocyte cell cycle progression.

中文翻译：

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褪黑激素激活 FIS1、DYN1 和 DYN2 恶性疟原​​虫相关基因进行线粒体裂变：Mitoemerald-GFP 作为可视化线粒体结构的工具。


疟疾导致全世界数百万人死亡，被认为是欠发达国家的巨大负担。对所有抗疟药产生耐药性的病例数量不断增加，使得新药的鉴定变得非常迫切。新型治疗干预的一个潜在非常有趣的目标是寄生虫线粒体。在这项工作中，我们研究了恶性疟原虫 3 个编码哺乳动物 FIS1（线粒体裂变蛋白 1）和 DRP1（动力相关蛋白 1）参与线粒体裂变的蛋白质同源物的基因。我们研究了恶性疟原虫基因的表达，这些基因与哺乳动物对应基因（即 FIS1、DYN1 和 DYN2）显示出充足的序列和结构同源性。编码的蛋白质的特征是在恶性疟原虫的整个红细胞周期中具有独特的表达模式，并且它们的 mRNA 通过用宿主激素褪黑激素处理寄生虫来调节。我们之前曾报道过，编码蛋白激酶 7 的疟原虫基因的敲除对于褪黑激素感应至关重要。我们在此表明​​，与野生型寄生虫相比，PfPk7 敲除会导致线粒体裂变基因表达的重大改变，并且在用宿主激素处理后裂变蛋白表达没有变化。最后，我们比较了野生型寄生虫和 PfPk7 敲除菌株中恶性疟原虫线粒体的形态特征（使用 MitoTracker Red CMX Ros）和耗氧特性。还开发了一种针对野生型寄生虫线粒体基质的新型 GFP 构建体，以可视化恶性疟原虫线粒体。我们在这里展示，P 的功能特征。 缺乏蛋白激酶 7 的细胞中恶性疟原虫发生了深刻的改变，表明这种酶在红细胞内细胞周期进展过程中控制线粒体形态发生和成熟方面发挥着重要作用。