Trypanosoma cruzi Epimastigotes Are Able to Manage Internal Cholesterol Levels under Nutritional Lipid Stress Conditions

Pereira, Miria G.; Visbal, Gonzalo; Salgado, Leonardo T.; Vidal, Juliana C.; Godinho, Joseane Lima Prado; Cicco, Nuccia N.T. De; Atella, Geórgia C.; Souza, Wanderley de; Cunha-e-Silva, Narcisa L.

doi:10.1371/journal.pone.0128949

Cited by 18 publications

(16 citation statements)

References 34 publications

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“…Even more notably, we showed that under these conditions, the lipids stored in lipid droplets [51,52] are consumed. Unlike what has been observed in procyclic forms of T. brucei, in which the function of lipid droplets is not clear [53], our results show that in T. cruzi, they are committed to epimastigote survival under extreme metabolic stress.…”

Section: Discussionmentioning

confidence: 81%

“…Here, we confirmed this finding by inhibiting the internal fatty acid consumption, which in turn diminished the oxidative phosphorylation activity, internal ATP levels and the total reductive activity of parasites under severe nutritional stress. Even more notably, we showed that under these conditions, the lipids stored in lipid droplets [51,52] are consumed. Unlike what has been observed in procyclic forms of T. brucei , in which the function of lipid droplets is not clear [53], our results show that in T. cruzi , they are committed to epimastigote survival under extreme metabolic stress.…”

Section: Discussionmentioning

confidence: 99%

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Fatty acid oxidation participates of the survival to starvation, cell cycle progression and differentiation in the insect stages of Trypanosoma cruzi

Souza

Damasceno

Marsiccobetre

et al. 2021

Preprint

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During its complex life cycle, Trypanosoma cruzi colonizes different niches in its insect and mammalian hosts. This characteristic determined the types of parasites that adapted to face challenging environmental cues. The primary environmental challenge, particularly in the insect stages, is poor nutrient availability. These T. cruzi stages could be exposed to fatty acids originating from the degradation of the perimicrovillar membrane. 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 via beta-oxidation. Lastly, we also show that fatty acids are degraded through beta-oxidation. Additionally, through beta-oxidation, electrons are fed directly to oxidative phosphorylation, and acetyl-CoA is supplied to the tricarboxylic acid cycle, which can be used to feed other anabolic pathways such as the de novo biosynthesis of fatty acids.Author SummaryTrypanosoma cruzi is a protist parasite with a life cycle involving two types of hosts, a vertebrate one (which includes humans, causing Chagas disease) and an invertebrate one (kissing bugs, which vectorize the infection among mammals). In both hosts, the parasite faces environmental challenges such as sudden changes in the metabolic composition of the medium in which they develop, severe starvation, osmotic stress and redox imbalance, among others. Because kissing bugs feed infrequently in nature, an intriguing aspect of T. cruzi biology (it exclusively inhabits the digestive tube of these insects) is how they subsist during long periods of starvation. In this work, we show that this parasite performs a metabolic switch from glucose consumption to lipid oxidation, and it is able to consume lipids and the lipid-derived fatty acids from both internal origins as well as externally supplied compounds. When fatty acid oxidation is chemically inhibited by etomoxir, a very well-known drug that inhibits the translocation of fatty acids into the mitochondria, the proliferative insect stage of the parasites has dramatically diminished survival under severe metabolic stress and its differentiation into its infective forms is impaired. Our findings place fatty acids in the centre of the scene regarding their extraordinary resistance to nutrient-depleted environments.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Fatty acid oxidation participates of the survival to starvation, cell cycle progression and differentiation in the insect stages of Trypanosoma cruzi

Souza

Damasceno

Marsiccobetre

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Here, we confirmed this finding by inhibiting the internal fatty acid consumption, which in turn diminished the oxidative phosphorylation activity, internal ATP levels and the total reductive activity of parasites under severe nutritional stress. Even more notably, we showed that under these conditions, the lipids stored in lipid droplets [ 58 , 59 ] are consumed. Unlike what has been observed in procyclic forms of T .…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2021

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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.

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“…Stained EECs were mounted on glass slides with UltraCruz® aqueous mounting medium (sc-24941, Santa Cruz Biotechnology, Dallas, Texas,USA) and examined using the Leica TCS SP5 II confocal microscope (488 nm excitation, 540 nm emission). Then the SOAT1 activity was measured [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

Embryonic cholesterol esterification is regulated by a cyclic AMP-dependent pathway in yolk sac membrane-derived endodermal epithelial cells

Wang

Lin

et al. 2017

PLoS ONE

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During avian embryonic development, endodermal epithelial cells (EECs) absorb yolk through the yolk sac membrane. Sterol O-acyltransferase (SOAT) is important for esterification and yolk lipid utilization during development. Because the major enzyme for yolk sac membrane cholesteryl ester synthesis is SOAT1, we cloned the avian SOAT1 promoter and elucidated the cellular functions of SOAT1. Treatments with either glucagon, isobutylmethylxanthine (IBMX), an adenylate cyclase activator (forskolin), a cAMP analog (dibutyryl-cAMP), or a low glucose concentration all increased SOAT1 mRNA accumulation in EECs from Japanese quail, suggesting that SOAT1 is regulated by nutrients and hormones through a cAMP-dependent pathway. Activity of protein kinase A (PKA) was increased by IBMX, whereas co-treatment with the PKA inhibitor, H89 negated the increase in PKA activity. Cyclic AMP-induced EECs had greater cholesterol esterification than untreated EECs. By promoter deletion and point-mutation, the cAMP-response element (-349 to -341 bp) was identified as critical in mediating transcription of SOAT1. In conclusion, expression of SOAT1 was regulated by a cAMP-dependent pathway and factors that increase PKA will increase SOAT1 to improve the utilization of lipids in the EECs and potentially modify embryonic growth.

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Trypanosoma cruzi Epimastigotes Are Able to Manage Internal Cholesterol Levels under Nutritional Lipid Stress Conditions

Cited by 18 publications

References 34 publications

Fatty acid oxidation participates of the survival to starvation, cell cycle progression and differentiation in the insect stages of Trypanosoma cruzi

Fatty acid oxidation participates of the survival to starvation, cell cycle progression and differentiation in the insect stages of Trypanosoma cruzi

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

Embryonic cholesterol esterification is regulated by a cyclic AMP-dependent pathway in yolk sac membrane-derived endodermal epithelial cells

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