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 Jill Painter Ponton, Michael W. Mather, Marcelo Jacobs-Lorena, Manuel Llinas, Akhil B. Vaidya

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)164-174
Number of pages11
JournalCell Reports
Volume11
Issue number1
DOIs
StatePublished - Apr 7 2015

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Tricarboxylic Acids
Plasmodium falciparum
Life Cycle Stages
Metabolism
Life cycle
Parasites
Antimalarials
Aconitate Hydratase
Citric Acid Cycle
Oocysts
Falciparum Malaria
Drug and Narcotic Control
Electron Transport
Culicidae
Isotopes
Mass spectrometry
Plasticity
Mass Spectrometry
Oxidoreductases
Blood

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ke, H., Lewis, I. A., Morrisey, J. M., McLean, K. J., Ganesan, S. M., Painter Ponton, H. J., ... Vaidya, A. B. (2015). Genetic investigation of tricarboxylic acid metabolism during the plasmodium falciparum life cycle. Cell Reports, 11(1), 164-174. https://doi.org/10.1016/j.celrep.2015.03.011
Ke, Hangjun ; Lewis, Ian A. ; Morrisey, Joanne M. ; McLean, Kyle J. ; Ganesan, Suresh M. ; Painter Ponton, Heather Jill ; Mather, Michael W. ; Jacobs-Lorena, Marcelo ; Llinas, Manuel ; Vaidya, Akhil B. / Genetic investigation of tricarboxylic acid metabolism during the plasmodium falciparum life cycle. In: Cell Reports. 2015 ; Vol. 11, No. 1. pp. 164-174.
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Ke, H, Lewis, IA, Morrisey, JM, McLean, KJ, Ganesan, SM, Painter Ponton, HJ, Mather, MW, Jacobs-Lorena, M, Llinas, M & Vaidya, AB 2015, 'Genetic investigation of tricarboxylic acid metabolism during the plasmodium falciparum life cycle', Cell Reports, vol. 11, no. 1, pp. 164-174. https://doi.org/10.1016/j.celrep.2015.03.011

Genetic investigation of tricarboxylic acid metabolism during the plasmodium falciparum life cycle. / Ke, Hangjun; Lewis, Ian A.; Morrisey, Joanne M.; McLean, Kyle J.; Ganesan, Suresh M.; Painter Ponton, Heather Jill; Mather, Michael W.; Jacobs-Lorena, Marcelo; Llinas, Manuel; Vaidya, Akhil B.

In: Cell Reports, Vol. 11, No. 1, 07.04.2015, p. 164-174.

Research output: Contribution to journalArticle

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Ke H, Lewis IA, Morrisey JM, McLean KJ, Ganesan SM, Painter Ponton HJ et al. Genetic investigation of tricarboxylic acid metabolism during the plasmodium falciparum life cycle. Cell Reports. 2015 Apr 7;11(1):164-174. https://doi.org/10.1016/j.celrep.2015.03.011