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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

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Autor(es):
Souza, Rodolpho Ornitz Oliveira [1] ; Damasceno, Flavia Silva [1] ; Marsiccobetre, Sabrina [1] ; Biran, Marc [2] ; Murata, Gilson [3] ; Curi, Rui [4] ; Bringaud, Frederic [5] ; Silber, Ariel Mariano [1]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Lab Biochem Tryps LaBTryps, Dept Parasitol, Inst Biomed Sci, Sao Paulo, SP - Brazil
[2] Univ Bordeaux, Ctr Resonance Magnet Systemes Biol RMSB, Bordeaux - France
[3] Univ Sao Paulo, Dept Physiol, Inst Biomed Sci, Sao Paulo, SP - Brazil
[4] Cruzeiro Univ, Interdisciplinary Postgrad Program Hlth Sci, Sao Paulo, SP - Brazil
[5] Univ Bordeaux, Lab Microbiol Fondamentale & Pathogen MFP, Bordeaux - France
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: PLOS PATHOGENS; v. 17, n. 4 APR 2021.
Citações Web of Science: 0
Resumo

Author summary Trypanosoma 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. 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-C-14]-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. (AU)

Processo FAPESP: 16/06034-2 - O papel biológico de aminoácidos e seus metabólitos derivados em Trypanosoma cruzi
Beneficiário:Ariel Mariano Silber
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 18/14432-3 - Uma rede para uma biologia integrativa em doenças negligenciadas: conectando a epigenética, o metabolismo e a biologia celular em tripanossomatídeos patogênicos
Beneficiário:Ariel Mariano Silber
Linha de fomento: Auxílio à Pesquisa - Temático