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Home / Malaria Research / Genetic Investigation of Tricarboxylic Acid Metabolism during the Plasmodium falciparum Life Cycle

Genetic Investigation of Tricarboxylic Acid Metabolism during the Plasmodium falciparum Life Cycle

April 2, 2015 By Malaria.com Leave a Comment

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 13C-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.

Authors / Source:
Hangjun Ke1, 5, Ian A. Lewis2, 5, 7, Joanne M. Morrisey1, Kyle J. McLean3, Suresh M. Ganesan1, 6, Heather J. Painter2, 8, Michael W. Mather1, Marcelo Jacobs-Lorena3, Manuel Llinás2, 4, 8, Akhil B. Vaidya1, ,
1 Center for Molecular Parasitology, Drexel University College of Medicine, Philadelphia, PA 19129, USA
2 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
3 Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA
4 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Received 23 October 2014, Revised 11 February 2015, Accepted 4 March 2015, Available online 2 April 2015

Download full text (PDF): Genetic Investigation of Tricarboxylic Acid Metabolism during the Plasmodium falciparum Life Cycle

Copyright 2015 Under a Creative Commons license

doi:10.1016/j.celrep.2015.03.011

Filed Under: Malaria Research

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