Dispensable Role of Mitochondrial Fission Protein 1 (Fis1) in the Erythrocytic Development of Plasmodium falciparum.
Dispensable Role of Mitochondrial Fission Protein 1 (Fis1) in the Erythrocytic Development of Plasmodium falciparum.
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DOI：
10.1128/msphere.00579-20
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发表时间：
2020-09-23
期刊：
影响因子：
4.8
通讯作者：
Ke H
中科院分区：
文献类型：
--
作者：
Maruthi M;Ling L;Zhou J;Ke H
疟疾每年造成2.3亿多临床病例和50万人死亡。疟疾寄生虫的单个线粒体在整个寄生虫的发育周期（DC）中充当代谢中心，并且在某些阶段也充当ATP的来源。为了传递其基本功能，寄生虫的线粒体需要在细胞分裂期间通过称为线粒体分裂的过程适当地分裂并分离到所有后代中。由于疟原虫属的不同性质，参与线粒体分裂的分子及其作用机制在很大程度上仍然未知。在这里，我们发现，唯一可识别的线粒体裂变衔接蛋白，是进化上保守的顶复门，Fis 1，它不是必需的恶性疟原虫无性阶段。我们的数据表明，疟疾寄生虫使用线粒体外膜上的冗余裂变衔接蛋白来介导裂变过程。疟疾仍然是一个巨大的全球健康负担，对这一疾病的控制遇到了严重的瓶颈。为了战胜疟疾并达到根除疟疾的目标，迫切需要深入了解寄生虫的生物学。疟疾寄生虫的寄生虫在整个寄生虫的生命周期中是必不可少的，并且已被验证为临床药物靶标。在疟原虫属的无性发育中，单个的纳米粒子从小的管状结构生长成复杂的分支网络。这种分枝的裂殖子在裂殖生殖末期分裂，产生8 - 32个子细胞，每个裂殖子分配一个分枝。在蚊子和肝脏阶段，巨大的线粒体网络被分成数千个片段，子线粒体被分离成单个后代。尽管线粒体分裂在疟原虫中具有重要意义，但其潜在机制在很大程度上是未知的。模型真核生物中线粒体分裂的研究已经揭示了几种线粒体分裂衔接蛋白参与募集发动蛋白GTP酶以物理地分裂线粒体膜。然而，顶复门寄生虫与酵母或人类没有可识别的线粒体裂变衔接蛋白同源物，除了Fis 1。在这里，我们调查的本地化和本质的Fis 1同源恶性疟原虫，PfFis 1（PF3D7_1325600），在无性生活周期。我们发现，PfFis 1需要一个完整的线粒体定位的C末端，但不是必不可少的寄生虫的发展或线粒体分裂。PfFis 1的转录作用表明疟原虫在线粒体外膜上含有额外的裂变衔接蛋白，这可能是线粒体裂变所必需的。重要性疟疾每年造成2.3亿多临床病例和50万人死亡。疟疾寄生虫的单个线粒体在整个寄生虫的发育周期（DC）中充当代谢中心，并且在某些阶段也充当ATP的来源。为了传递其基本功能，寄生虫的线粒体需要在细胞分裂期间通过称为线粒体分裂的过程适当地分裂并分离到所有后代中。由于疟原虫属的不同性质，参与线粒体分裂的分子及其作用机制在很大程度上仍然未知。在这里，我们发现，唯一可识别的线粒体裂变衔接蛋白，是进化上保守的顶复门，Fis 1，它不是必需的恶性疟原虫无性阶段。我们的数据表明，疟疾寄生虫使用线粒体外膜上的冗余裂变衔接蛋白来介导裂变过程。
Malaria is responsible for over 230 million clinical cases and ∼half a million deaths each year. The single mitochondrion of the malaria parasite functions as a metabolic hub throughout the parasite’s developmental cycle (DC) and also as a source of ATP in certain stages. To pass on its essential functions, the parasite’s mitochondrion needs to be properly divided and segregated into all progeny during cell division via a process termed mitochondrial fission. Due to the divergent nature of Plasmodium spp., the molecular players involved in mitochondrial fission and their mechanisms of action remain largely unknown. Here, we found that the only identifiable mitochondrial fission adaptor protein that is evolutionarily conserved in the Apicomplexan phylum, Fis1, it not essential in P. falciparum asexual stages. Our data suggest that malaria parasites use redundant fission adaptor proteins on the mitochondrial outer membrane to mediate the fission process. Malaria remains a huge global health burden, and control of this disease has run into a severe bottleneck. To defeat malaria and reach the goal of eradication, a deep understanding of the parasite biology is urgently needed. The mitochondrion of the malaria parasite is essential throughout the parasite’s life cycle and has been validated as a clinical drug target. In the asexual development of Plasmodium spp., the single mitochondrion grows from a small tubular structure to a complex branched network. This branched mitochondrion is divided at the end of schizogony when 8 to 32 daughter cells are produced, distributing one mitochondrion to each forming merozoite. In mosquito and liver stages, the giant mitochondrial network is split into thousands of pieces and daughter mitochondria are segregated into individual progeny. Despite the significance of mitochondrial fission in Plasmodium, the underlying mechanism is largely unknown. Studies of mitochondrial fission in model eukaryotes have revealed that several mitochondrial fission adaptor proteins are involved in recruiting dynamin GTPases to physically split mitochondrial membranes. Apicomplexan parasites, however, share no identifiable homologs of mitochondrial fission adaptor proteins with yeast or humans, except for Fis1. Here, we investigated the localization and essentiality of the Fis1 homolog in Plasmodium falciparum, PfFis1 (PF3D7_1325600), during the asexual life cycle. We found that PfFis1 requires an intact C terminus for mitochondrial localization but is not essential for parasite development or mitochondrial fission. The dispensable role of PfFis1 indicates that Plasmodium contains additional fission adaptor proteins on the mitochondrial outer membrane that could be essential for mitochondrial fission. IMPORTANCE Malaria is responsible for over 230 million clinical cases and ∼half a million deaths each year. The single mitochondrion of the malaria parasite functions as a metabolic hub throughout the parasite’s developmental cycle (DC) and also as a source of ATP in certain stages. To pass on its essential functions, the parasite’s mitochondrion needs to be properly divided and segregated into all progeny during cell division via a process termed mitochondrial fission. Due to the divergent nature of Plasmodium spp., the molecular players involved in mitochondrial fission and their mechanisms of action remain largely unknown. Here, we found that the only identifiable mitochondrial fission adaptor protein that is evolutionarily conserved in the Apicomplexan phylum, Fis1, it not essential in P. falciparum asexual stages. Our data suggest that malaria parasites use redundant fission adaptor proteins on the mitochondrial outer membrane to mediate the fission process.