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Procyclic trypanosomes recycle glucose catabolites and TCA cycle intermediates to stimulate growth in the presence of physiological amounts of proline
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SYSNO ASEP 0555227 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Procyclic trypanosomes recycle glucose catabolites and TCA cycle intermediates to stimulate growth in the presence of physiological amounts of proline Author(s) Villafraz, O. (FR)
Biran, M. (FR)
Pineda, E. (FR)
Plazolles, N. (FR)
Cahoreau, E. (FR)
Souza, R.O.O. (BR)
Thonnus, M. (FR)
Allmann, S. (DE)
Tetaud, E. (FR)
Riviere, L. (FR)
Silber, A. (BR)
Barrett, M. (GB)
Zíková, Alena (BC-A) RID, ORCID
Boshart, M. (DE)
Portais, J. (FR)
Bringaud, F. (FR)Number of authors 16 Article number e1009204 Source Title PLoS Pathogens. - : Public Library of Science - ISSN 1553-7366
Roč. 17, č. 3 (2021)Number of pages 28 s. Publication form Online - E Language eng - English Country US - United States Keywords inducible expression system ; succinate coa-transferase ; energy-metabolism ; blood-stream ; molecular characterization ; lipid biosynthesis ; brucei ; acetate ; mitochondrion ; enzyme Subject RIV EA - Cell Biology OECD category Cell biology R&D Projects GA20-14409S GA ČR - Czech Science Foundation (CSF) EF16_019/0000759 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support BC-A - RVO:60077344 UT WOS 000625321100005 EID SCOPUS 85102908208 DOI 10.1371/journal.ppat.1009204 Annotation Trypanosoma brucei, a protist responsible for human African trypanosomiasis (sleeping sickness), is transmitted by the tsetse fly where the procyclic forms of the parasite develop in the proline-rich (1-2 mM) and glucose-depleted digestive tract. Proline is essential for the midgut colonization of the parasite in the insect vector, however other carbon sources could be available and used to feed its central metabolism. Here we show that procyclic trypanosomes can consume and metabolize metabolic intermediates, including those excreted from glucose catabolism (succinate, alanine and pyruvate), with the exception of acetate, which is the ultimate end-product excreted by the parasite. Among the tested metabolites, tricarboxylic acid (TCA) cycle intermediates (succinate, malate and alpha-ketoglutarate) stimulated growth of the parasite in the presence of 2 mM proline. The pathways used for their metabolism were mapped by proton-NMR metabolic profiling and phenotypic analyses of thirteen RNAi and/or null mutants affecting central carbon metabolism. We showed that (i) malate is converted to succinate by both the reducing and oxidative branches of the TCA cycle, which demonstrates that procyclic trypanosomes can use the full TCA cycle, (ii) the enormous rate of alpha-ketoglutarate consumption (15-times higher than glucose) is possible thanks to the balanced production and consumption of NADH at the substrate level and (iii) alpha-ketoglutarate is toxic for trypanosomes if not appropriately metabolized as observed for an alpha-ketoglutarate dehydrogenase null mutant. In addition, epimastigotes produced from procyclics upon overexpression of RBP6 showed a growth defect in the presence of 2 mM proline, which is rescued by alpha-ketoglutarate, suggesting that physiological amounts of proline are not sufficient per se for the development of trypanosomes in the fly. In conclusion, these data show that trypanosomes can metabolize multiple metabolites, in addition to proline, which allows them to confront challenging environments in the fly. Workplace Biology Centre (since 2006) Contact Dana Hypšová, eje@eje.cz, Tel.: 387 775 214 Year of Publishing 2022 Electronic address https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009204
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