Procyclic trypanosomes recycle glucose catabolites and TCA cycle intermediates to stimulate growth in the presence of physiological amounts of proline

Trypanosoma brucei , a protist responsible for human African trypanosomiasis (sleeping sickness), is transmitted by the tsetse fly where procyclic forms of parasite develop in proline-rich (1–2 mM) and glucose-depleted digestive tract. Proline essential midgut colonization insect vector, however other carbon sources could be available used to feed its central metabolism. Here we show that trypanosomes can consume metabolize metabolic intermediates, including those excreted from glucose catabolism (succinate, alanine pyruvate), with exception acetate, which ultimate end-product parasite. Among tested metabolites, tricarboxylic acid (TCA) cycle intermediates malate α-ketoglutarate) stimulated growth presence 2 mM proline. The pathways their metabolism were mapped proton-NMR profiling phenotypic analyses thirteen RNAi and/or null mutants affecting We showed ( i ) converted succinate both reducing oxidative branches TCA cycle, demonstrates use full ii enormous rate α-ketoglutarate consumption (15-times higher than glucose) possible thanks balanced production NADH at substrate level iii toxic if not appropriately metabolized as observed an dehydrogenase mutant. In addition, epimastigotes produced procyclics upon overexpression RBP6 defect proline, rescued α-ketoglutarate, suggesting physiological amounts proline are sufficient per se development fly. conclusion, these data multiple addition allows them confront challenging environments