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

ABSTRACT:

Mitochondrial metabolic remodeling is a hallmark of the Trypanosoma brucei digenetic life cycle since the insect stage utilizes the cost-effective oxidative phosphorylation to generate ATP, while bloodstream cells switch to less energetically efficient aerobic glycolysis. Due to difficulties in acquiring enough parasites from the tsetse fly vector for biochemical analysis, the dynamics of the parasite´s mitochondrial 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 a mitochondrial alternative oxidase, an increase in proline consumption and its oxidation, elevated activity of complex II and certain TCA cycle enzymes, which led to mitochondrial inner membrane hyperpolarization and increased ROS levels in both mitochondrion and cytosol. Interestingly, these ROS molecules acted as signaling molecules driving developmental progression since exogenous expression of catalase, a ROS scavenger, halted the in vitro-induced cell 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.

Data availability:

RNA-Seq

Proteomic data associated with this study are available in the PRIDE repository: accession number PXD016370.

INSTRUMENT(S): Liquid Chromatography MS - Alternating (LC-MS (Alternating))

SUBMITTER: Clement Regnault 

PROVIDER: MTBLS1390 | MetaboLights | 2020-08-20

REPOSITORIES: MetaboLights