Mitochondrial ATP synthase is dispensable in blood-stage Plasmodium berghei rodent malaria but essential in the mosquito phase
Mitochondrial ATP synthase is dispensable in blood-stage Plasmodium berghei rodent malaria but essential in the mosquito phase
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DOI：
10.1073/pnas.1423959112
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发表时间：
2015-08-18
影响因子：
11.1
通讯作者：
McFadden, Geoffrey I.
中科院分区：
文献类型：
--
作者：
Sturm, Angelika;Mollard, Vanessa;McFadden, Geoffrey I.
线粒体ATP合酶由糖酵解产生的丙酮酸的化学渗透氧化驱动。血液阶段的疟疾寄生虫避免化学渗透，而几乎完全依赖于糖酵解产生ATP，这就引出了一个问题，即线粒体ATP合酶在寄生虫生命周期的血液阶段是否是必需的。我们敲除了啮齿类疟疾寄生虫伯氏疟原虫（Plasmodium berghei）的线粒体ATP合成酶β亚基基因，消除了将ADP转化为ATP的蛋白质。ATP合酶β亚基基因的破坏仅略微降低了无性血液阶段寄生虫的生长，但完全阻断了通过斯氏按蚊蚊子的小鼠间传播。缺乏ATP合酶β亚基基因的寄生虫产生能存活的配子，配子融合并形成动合子，但不能超过这个阶段。缺乏ATP合酶β亚基基因的动合子具有正常的运动性，但在蚊子中肠中不能存活，并且从未产生卵囊或子孢子，从而消除了通过蚊子叮咬向幼稚小鼠的传播。我们将自身不育的ATP合酶β亚基敲除寄生虫与伯氏疟原虫的雄性缺陷、自身不育株杂交，其恢复了生育力和卵囊和子孢子的产生，这表明线粒体ATP合酶对于伯氏疟原虫中通过雌性携带疟原虫的有性生殖系的持续生存力是必不可少的。ATP合酶的扰动完全阻断了向蚊子媒介的传播，并可能成为疾病控制的潜在目标。
Mitochondrial ATP synthase is driven by chemiosmotic oxidation of pyruvate derived from glycolysis. Blood-stage malaria parasites eschew chemiosmosis, instead relying almost solely on glycolysis for their ATP generation, which begs the question of whether mitochondrial ATP synthase is necessary during the blood stage of the parasite life cycle. We knocked out the mitochondrial ATP synthase beta subunit gene in the rodent malaria parasite, Plasmodium berghei, ablating the protein that converts ADP to ATP. Disruption of the beta subunit gene of the ATP synthase only marginally reduced asexual blood-stage parasite growth but completely blocked mouse-to-mouse transmission via Anopheles stephensi mosquitoes. Parasites lacking the beta subunit gene of the ATP synthase generated viable gametes that fuse and form ookinetes but cannot progress beyond this stage. Ookinetes lacking the beta subunit gene of the ATP synthase had normal motility but were not viable in the mosquito midgut and never made oocysts or sporozoites, thereby abrogating transmission to naive mice via mosquito bite. We crossed the self-infertile ATP synthase beta subunit knockout parasites with a male-deficient, self-infertile strain of P. berghei, which restored fertility and production of oocysts and sporozoites, which demonstrates that mitochondrial ATP synthase is essential for ongoing viability through the female, mitochondrion-carrying line of sexual reproduction in P. berghei malaria. Perturbation of ATP synthase completely blocks transmission to the mosquito vector and could potentially be targeted for disease control.