Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, UK.
Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, Giessen, Germany.
Commun Biol. 2024 Nov 16;7(1):1525. doi: 10.1038/s42003-024-07240-z.
Plasmodium male and female gametocytes are the gatekeepers of human-to-mosquito transmission, therefore essential for propagation of malaria within a population. Whilst dormant in humans, their divergent roles during transmission become apparent soon after mosquito feeding with a rapid transformation into gametes - males forming eight motile sperm-like cells aiming to fertilise a single female gamete. Little is known about how the parasite fuels this abrupt change, and the potential role played by their large and elaborate cristate mitochondrion. Using a sex-specific antibody and functional mitochondrial labelling, we show that the male gametocyte mitochondrion is less active than that of female gametocytes and more sensitive to antimalarials targeting mitochondrial energy metabolism. Rather than a vestigial organelle discarded during male gametogenesis, we demonstrate that mitochondrial ATP synthesis is essential for its completion. Additionally, using a genetically encoded ratiometric ATP sensor, we show that gametocytes can maintain cytoplasmic ATP homeostasis in the absence of mitochondrial respiration, indicating the essentiality of the gametocyte mitochondrion for transmission alone. Together, this reveals how gametocytes responsively balance the conflicting demands of a dormant and active lifestyle, highlighting the mitochondria as a rich source of transmission-blocking targets for future drug development.
疟原虫雄配子体和雌配子体是人类向蚊子传播的守门员，因此对疟疾在人群中的传播至关重要。虽然在人体内处于休眠状态，但在蚊子吸食后，它们在传播过程中的不同作用很快就会显现出来，迅速转化为配子体——雄性形成 8 个游动的精子样细胞，旨在使单个雌性配子受精。对于寄生虫如何为这种突然的变化提供动力，以及它们庞大而复杂的栉状线粒体可能发挥的作用，人们知之甚少。我们使用一种性别特异性抗体和功能性线粒体标记，表明雄配子体的线粒体不如雌配子体活跃，并且对针对线粒体能量代谢的抗疟药物更敏感。我们证明，线粒体 ATP 合成对于完成雄配子体的形成是必不可少的，而不是在雄性配子发生过程中丢弃的退化细胞器。此外，我们使用遗传编码的比率型 ATP 传感器表明，配子体可以在没有线粒体呼吸的情况下维持细胞质 ATP 动态平衡，这表明配子体线粒体对于传播是必不可少的。综上所述，这揭示了配子体如何响应性地平衡休眠和活跃生活方式的冲突需求，突出了线粒体作为未来药物开发中阻断传播的靶标丰富来源。
