Ke Hangjun, Lewis Ian A, Morrisey Joanne M, McLean Kyle J, Ganesan Suresh M, Painter Heather J, Mather Michael W, Jacobs-Lorena Marcelo, Llinás Manuel, Vaidya Akhil B
Center for Molecular Parasitology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Cell Rep. 2015 Apr 7;11(1):164-74. doi: 10.1016/j.celrep.2015.03.011. Epub 2015 Apr 2.
New antimalarial drugs are urgently needed to control drug-resistant forms of the malaria parasite Plasmodium falciparum. Mitochondrial electron transport is the target of both existing and new antimalarials. Herein, we describe 11 genetic knockout (KO) lines that delete six of the eight mitochondrial tricarboxylic acid (TCA) cycle enzymes. Although all TCA KOs grew normally in asexual blood stages, these metabolic deficiencies halted life-cycle progression in later stages. Specifically, aconitase KO parasites arrested as late gametocytes, whereas α-ketoglutarate-dehydrogenase-deficient parasites failed to develop oocysts in the mosquitoes. Mass spectrometry analysis of (13)C-isotope-labeled TCA mutant parasites showed that P. falciparum has significant flexibility in TCA metabolism. This flexibility manifested itself through changes in pathway fluxes and through altered exchange of substrates between cytosolic and mitochondrial pools. Our findings suggest that mitochondrial metabolic plasticity is essential for parasite development.
迫切需要新型抗疟药物来控制耐药形式的恶性疟原虫。线粒体电子传递是现有和新型抗疟药物的作用靶点。在此，我们描述了11个基因敲除（KO）品系，这些品系缺失了八种线粒体三羧酸（TCA）循环酶中的六种。尽管所有TCA基因敲除品系在无性血液阶段生长正常，但这些代谢缺陷在后期阶段阻止了生命周期的进展。具体而言，乌头酸酶基因敲除的寄生虫停滞在晚期配子体阶段，而α-酮戊二酸脱氢酶缺陷的寄生虫在蚊子体内无法发育成卵囊。对（13）C同位素标记的TCA突变寄生虫进行质谱分析表明，恶性疟原虫在TCA代谢方面具有显著的灵活性。这种灵活性通过途径通量的变化以及胞质和线粒体池之间底物交换的改变得以体现。我们的研究结果表明，线粒体代谢可塑性对寄生虫发育至关重要。
