Genetic Investigation of Tricarboxylic Acid Metabolism during the Plasmodium falciparum Life Cycle
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Ke-2015-Genetic investigatio.pdf
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Author(s)
Ke, Hangjun
Lewis, Ian A.
Morrisey, Joanne M.
McLean, Kyle J.
Painter, Heather J.
Mather, Michael W.
Jacobs-Lorena, Marcelo
Vaidya, Akhil B.
Maddur Ganesan, Suresh
Llinas, Manuel
Date Issued
April 2015
Journal
Cell Reports
Publisher
Elsevier
Citation
Ke, Hangjun, Ian A. Lewis, Joanne M. Morrisey, Kyle J. McLean, Suresh M. Ganesan, Heather J. Painter, Michael W. Mather, Marcelo Jacobs-Lorena, Manuel Llinas, and Akhil B. Vaidya. “Genetic Investigation of Tricarboxylic Acid Metabolism During the Plasmodium Falciparum Life Cycle.” Cell Reports 11, no. 1 (April 2015): 164–174.
Version
Final published version
Abstract
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 [superscript 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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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DOI of Published Version
https://doi.org/10.1016/j.celrep.2015.03.011
