Fatty acid oxidation participates in resistance to nutrient-depleted environments in the insect stages of Trypanosoma cruzi

Abstract

Trypanosoma cruzi, the parasite causing Chagas disease, is a digenetic flagellated protist that infects mammals (including humans) and reduviid insect vectors. Therefore, T. cruzi must colonize different niches in order to complete its life cycle in both hosts. This fact determines the need of adaptations to face challenging environmental cues. The primary environmental challenge, particularly in the insect stages, is poor nutrient availability. In this regard, it is well known that T. cruzi has a flexible metabolism able to rapidly switch from carbohydrates (mainly glucose) to amino acids (mostly proline) consumption. Also established has been the capability of T. cruzi to use glucose and amino acids to support the differentiation process occurring in the insect, from replicative non-infective epimastigotes to non-replicative infective metacyclic trypomastigotes. However, little is known about the possibilities of using externally available and internally stored fatty acids as resources to survive in nutrient-poor environments, and to sustain metacyclogenesis. In this study, we revisit the metabolic fate of fatty acid breakdown in T. cruzi. Herein, we show that during parasite proliferation, the glucose concentration in the medium can regulate the fatty acid metabolism. At the stationary phase, the parasites fully oxidize fatty acids. [U-14C]-palmitate can be taken up from the medium, leading to CO2 production. Additionally, we show that electrons are fed directly to oxidative phosphorylation, and acetyl-CoA is supplied to the tricarboxylic acid (TCA) cycle, which can be used to feed anabolic pathways such as the de novo biosynthesis of fatty acids. Finally, we show as well that the inhibition of fatty acids mobilization into the mitochondrion diminishes the survival to severe starvation, and impairs metacyclogenesis.

Metabolic Alteration of Trypanosoma cruzi during Differentiation of Epimastigote to Trypomastigote Forms

“…The endogenous energy reserve present in various evolutive forms of T. cruzi has been attributed to carbohydrates [19]. However, while epimastigotes can interchange glucose and amino acids, they also can accumulate fatty acids into lipid droplets during growth and use this reserve to support its growth after glucose exhaustion [13,48,49]. Furthermore, this same study demonstrated that the insect stages coordinate the activation of fatty acid consumption with the metabolism of glucose [48].…”

Clethra fimbriata hexanic extract triggers alteration in the energy metabolism in epimastigotes of Trypanosoma cruzi

“…The effects observed on processes related to carbohydrate and amino acid-dependent energy production in epimastigotes are like those reported after nutritional stress induced by long periods of starvation. Souza et al evaluated the role of FA oxidation after depriving T. cruzi epimastigotes cultures of glucose, finding that, in the absence of glucose, lipid droplets become the main sources of FA, which help the body survive nutritional stress by producing acetyl-CoA that fuels TAC, contributing to mitochondrial ATP production ( Souza et al, 2021 ). In summary, epimastigotes use FA as carbon and energy source when glucose and amino acids are not available.…”

Small molecule mediators of host-T. cruzi-environment interactions in Chagas disease

“…Indeed, triatomine guts and feces contain a diverse range of chemical classes, with lipids the most abundant [11,27]. Free fatty acids are an important energy source for T. cruzi epimastigotes, if glucose is limiting, and are sufficient to induce T. cruzi development from epimastigotes to metacyclic trypomastigotes [28][29][30]. Purines and pyrimidines are present and may serve as sources for parasite proliferation.…”