Cell Reports
Volume 11, Issue 1, 7 April 2015, Pages 164-174
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Genetic Investigation of Tricarboxylic Acid Metabolism during the Plasmodium falciparum Life Cycle

https://doi.org/10.1016/j.celrep.2015.03.011Get rights and content
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Highlights

  • Six of the eight TCA cycle enzymes were knocked out without affecting asexual growth

  • Metabolic labeling was analyzed in nine TCA KOs via 13C-labeling and mass spectrometry

  • The TCA cycle is adaptable, and the effect of a disrupted TCA cycle is stage specific

Summary

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.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Co-first author

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Present address: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

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Present address: Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada

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Present address: Department of Biochemistry and Molecular Biology and Center for Malaria Research, Penn State University, State College, PA 16802, USA