Suramin exposure alters cellular metabolism and mitochondrial energy production in African trypanosomes

Zoltner, M. et al. (2020) Suramin exposure alters cellular metabolism and mitochondrial energy production in African trypanosomes. Journal of Biological Chemistry, 295(24), pp. 8331-8347. (doi: 10.1074/jbc.ra120.012355) (PMID:32354742) (PMCID:PMC7294092)

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Abstract

Introduced about a century ago, suramin remains a frontline drug for the management of early-stage East African trypanosomiasis (sleeping sickness). Cellular entry into the causative agent, the protozoan parasite Trypanosoma brucei, occurs through receptor-mediated endocytosis involving the parasite's invariant surface glycoprotein 75 (ISG75), followed by transport into the cytosol via a lysosomal transporter. The molecular basis of the trypanocidal activity of suramin remains unclear, but some evidence suggests broad, but specific, impacts on trypanosome metabolism (i.e. polypharmacology). Here we observed that suramin is rapidly accumulated in trypanosome cells proportionally to ISG75 abundance. Although we found little evidence that suramin disrupts glycolytic or glycosomal pathways, we noted increased mitochondrial ATP production, but a net decrease in cellular ATP levels. Metabolomics highlighted additional impacts on mitochondrial metabolism, including partial Krebs' cycle activation and significant accumulation of pyruvate, corroborated by increased expression of mitochondrial enzymes and transporters. Significantly, the vast majority of suramin-induced proteins were normally more abundant in the insect forms compared with the blood stage of the parasite, including several proteins associated with differentiation. We conclude that suramin has multiple and complex effects on trypanosomes, but unexpectedly partially activates mitochondrial ATP-generating activity. We propose that despite apparent compensatory mechanisms in drug-challenged cells, the suramin-induced collapse of cellular ATP ultimately leads to trypanosome cell death.

Item Type:Articles
Additional Information:This work was supported by Wellcome Trust Grant 204697/Z/16/Z (to M.C.F.) and Medical Research Council Grant MR/P009018/1 (to M.C.F.). M.C.F. and D.H. are Wellcome Trust investigators. F.A. was supported by Leverhulme Trust Early Career Fellowship ECF-2015-392. M.P.B. was supported by Wellcome Trust Grant 104111/Z/14/Z. M.C. was supported by a post-lauream fellowship from the University of Bologna, Italy. G.D.C. received a Ph.D. scholarship from Science Without Borders (206385/2014-5, CNPq, Brazil). A.Z. was supported by Grant 17-22248S and ERD Fund Grant CZ.02.1.01/0.0/0.0/16_019/0000759 Czech Academy of Science.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:cerone, michela and Achcar, Dr Fiona and Campagnaro, Gustavo and De Koning, Professor Harry and Barrett, Professor Michael
Creator Roles:
Campagnaro, G.Investigation
Cerone, M.Investigation, Formal analysis
Achcar, F.Formal analysis
Barrett, M.Conceptualization, Writing – original draft, Formal analysis, Supervision
De Koning, H.Investigation, Writing – original draft, Formal analysis
Authors: Zoltner, M., Campagnaro, G. D., Taleva, G., Burrell, A., Cerone, M., Leung, K.-F., Achcar, F., Horn, D., Vaughan, S., Gadelha, C., Zíková, A., Barrett, M. P., De Koning, H. P., and Field, M. C.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Biological Chemistry
Publisher:Elsevier
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:30 April 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Journal of Biological Chemistry 295(24):8331-8347
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172213Metabolic subversion in the interaction between leishmania and the macrophageFiona AchcarLeverhulme Trust (LEVERHUL)ECF-2015-392Institute of Infection, Immunity & Inflammation
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZIII - Parasitology