Micchelli Chiara E, Percopo Caroline, Traver Maria, Brzostowski Joseph, Amin Shuchi N, Prigge Sean T, Sá Juliana M, Wellems Thomas E
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
PNAS Nexus. 2024 Sep 24;3(10):pgae424. doi: 10.1093/pnasnexus/pgae424. eCollection 2024 Oct.
Morphological modifications and shifts in organelle relationships are hallmarks of dormancy in eukaryotic cells. Communications between altered mitochondria and nuclei are associated with metabolic quiescence of cancer cells that can survive chemotherapy. In plants, changes in the pathways between nuclei, mitochondria, and chloroplasts are associated with cold stress and bud dormancy. parasites, the deadliest agent of malaria in humans, contain a chloroplast-like organelle (apicoplast) derived from an ancient photosynthetic symbiont. Antimalarial treatments can fail because a fraction of the blood-stage parasites enter dormancy and recrudesce after drug exposure. Altered mitochondrial-nuclear interactions in these persisters have been described for , but interactions of the apicoplast remained to be characterized. In the present study, we examined the apicoplasts of persisters obtained after exposure to dihydroartemisinin (a first-line antimalarial drug) followed by sorbitol treatment, or after exposure to sorbitol treatment alone. As previously observed, the mitochondrion of persisters was consistently enlarged and in close association with the nucleus. In contrast, the apicoplast varied from compact and oblate, like those of active ring-stage parasites, to enlarged and irregularly shaped. Enlarged apicoplasts became more prevalent later in dormancy, but regular size apicoplasts subsequently predominated in actively replicating recrudescent parasites. All three organelles, nucleus, mitochondrion, and apicoplast, became closer during dormancy. Understanding their relationships in erythrocytic-stage persisters may lead to new strategies to prevent recrudescences and protect the future of malaria chemotherapy.
细胞器关系的形态学改变和变化是真核细胞休眠的标志。线粒体与细胞核之间的通讯改变与能够在化疗中存活的癌细胞的代谢静止有关。在植物中，细胞核、线粒体和叶绿体之间通路的变化与冷胁迫和芽休眠有关。疟原虫是人类疟疾最致命的病原体，它含有一种源自古老光合共生体的类叶绿体细胞器（顶质体）。抗疟治疗可能会失败，因为一部分血液阶段的疟原虫进入休眠状态，并在接触药物后复发。已经描述了这些持续性疟原虫中线粒体 - 细胞核相互作用的改变，但顶质体的相互作用仍有待表征。在本研究中，我们检查了在接触双氢青蒿素（一种一线抗疟药物）后再进行山梨醇处理，或仅进行山梨醇处理后获得的持续性疟原虫的顶质体。如先前观察到的，持续性疟原虫的线粒体持续增大并与细胞核紧密相连。相比之下，顶质体的形态各异，从紧凑扁平状（类似于活跃环状阶段疟原虫的顶质体）到增大且形状不规则。增大的顶质体在休眠后期变得更为普遍，但正常大小的顶质体随后在活跃复制的复发疟原虫中占主导地位。在休眠期间，细胞核、线粒体和顶质体这三种细胞器之间的距离变得更近。了解它们在红细胞阶段持续性疟原虫中的关系可能会带来预防复发和保护疟疾化疗未来的新策略。
