Cell-based and multi-omics profiling reveals dynamic metabolic repurposing of mitochondria to drive developmental progression of Trypanosoma brucei

Doleželová, E., Kunzová, M., Dejung, M., Levin, M., Panicucci, B., Regnault, C., Janzen, C. J., Barrett, M. P. , Butter, F. and Zíková, A. (2020) Cell-based and multi-omics profiling reveals dynamic metabolic repurposing of mitochondria to drive developmental progression of Trypanosoma brucei. PLoS Biology, 18(6), e3000741. (doi: 10.1371/journal.pbio.3000741) (PMID:32520929) (PMCID:PMC7307792)

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Abstract

Mitochondrial metabolic remodeling is a hallmark of the Trypanosoma brucei digenetic life cycle because the insect stage utilizes a cost-effective oxidative phosphorylation (OxPhos) to generate ATP, while bloodstream cells switch to aerobic glycolysis. Due to difficulties in acquiring enough parasites from the tsetse fly vector, the dynamics of the parasite’s metabolic rewiring in the vector have remained obscure. Here, we took advantage of in vitro–induced differentiation to follow changes at the RNA, protein, and metabolite levels. This multi-omics and cell-based profiling showed an immediate redirection of electron flow from the cytochrome-mediated pathway to an alternative oxidase (AOX), an increase in proline consumption, elevated activity of complex II, and certain tricarboxylic acid (TCA) cycle enzymes, which led to mitochondrial membrane hyperpolarization and increased reactive oxygen species (ROS) levels. Interestingly, these ROS molecules appear to act as signaling molecules driving developmental progression because ectopic expression of catalase, a ROS scavenger, halted the in vitro–induced differentiation. Our results provide insights into the mechanisms of the parasite’s mitochondrial rewiring and reinforce the emerging concept that mitochondria act as signaling organelles through release of ROS to drive cellular differentiation.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Regnault, Mr Clement and Barrett, Professor Michael
Creator Roles:
Regnault, C.Data curation, Formal analysis
Barrett, M. P.Data curation, Formal analysis, Funding acquisition, Resources, Writing – original draft, Writing – review and editing
Authors: Doleželová, E., Kunzová, M., Dejung, M., Levin, M., Panicucci, B., Regnault, C., Janzen, C. J., Barrett, M. P., Butter, F., and Zíková, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Biology
Publisher:Public Library of Science
ISSN:1544-9173
ISSN (Online):1545-7885
Published Online:10 June 2020
Copyright Holders:Copyright © 2020 Doleželová et al.
First Published:First published in PLoS Biology 18(6): e3000741
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZRIII - Parasitology