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Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle
Journal article   Open access   Peer reviewed

Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle

Hangjun Ke, Ian A Lewis, Joanne M Morrisey, Kyle J McLean, Suresh M Ganesan, Heather J Painter, Michael W Mather, Marcelo Jacobs-Lorena, Manuel Llinás and Akhil B Vaidya
Cell reports (Cambridge), v 11(1)
07 Apr 2015
DOI: https://doi.org/10.1016/j.celrep.2015.03.011
PMID: 25843709
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1016/j.celrep.2015.03.011View
Published, Version of Record (VoR)CC BY-NC-ND V4.0,  Open

Abstract

Animals Antimalarials - chemistry Antimalarials - isolation & purification Antimalarials - metabolism Citric Acid Cycle - genetics Enzymes - genetics Enzymes - metabolism Erythrocytes - metabolism Gene Knockout Techniques Humans Life Cycle Stages Malaria, Falciparum - drug therapy Malaria, Falciparum - enzymology Malaria, Falciparum - genetics Malaria, Falciparum - parasitology Mitochondria - metabolism Mitochondria - pathology Plasmodium falciparum - enzymology Plasmodium falciparum - genetics Plasmodium falciparum - growth & development Plasmodium falciparum - pathogenicity Tricarboxylic Acids - metabolism
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.

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130 citations in Web of Science
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Collaboration types
Domestic collaboration
Web of Science research areas
Cell Biology
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