The role of the mitochondrial and glycosomal isoforms of fumarate reductase of Trypanosoma Cruzi

• Grant number: 17/16553-0
• Support Opportunities: Research Grants - Visiting Researcher Grant - International
• Start date: October 29, 2017
• End date: November 22, 2017
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Ariel Mariano Silber
• Grantee: Ariel Mariano Silber
• Visiting researcher: Paul Michels
• Visiting researcher institution: University of Edinburgh, Scotland
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 16/06034-2 - The biological role of amino acids and their metabolites in Trypanosoma cruzi, AP.TEM

Abstract

Trypanosomatids are deficient in some of the components of the Complex I of the respiratory chain. This limits the cell ability to re-oxidize NADH to keep an adequate ratio NAD+/NADH, which in turn is critical for a normal functionality of critical metabolic pathways, such as glycolysis. Epimastigotes of Trypanosoma cruzi, the etiological agent for Chagas disease, are able to metabolize glucose during their exponential growth phase, with the production of reduced metabolites, such as succinate as end products. It was shown that succinate derives from the reduction of fumarate inside and outside the mitochondria through fumarate reductase activities. A glycosomal isoform of fumarate reductase was already shown in T. brucei, however, its presence in this organelle in T. cruzi was not shown yet. It is also not established how much the glycosome and the mitochondria contribute to the production of secreted succinate. In this context, we propose as a hypothesis that the relationship between glycosomal and mitochondrial fumarate reductase would contribute to regulate the NAD+/NADH ratio in these two organelles. In addition, given the impermeability of glycosomes to NAD+/NADH, and its permeability to fumarate/succinate, the ratio among the latter would be determinant in the "exchange of information" about the redox state in both compartments. This project aims to develop a set of exploratory experiments to have a preliminary evaluation of the sustainability of the proposed hypothesis. Prof. Paul Michels has the expertise to obtain, purify and analyse intact glycosomes as well as their components. This expertise, combined with our experience in mitochondrial physiology, will be fundamental to obtain preliminary data to improve our knowledgment on the relationship and "metabolic communication" between the glycosome and the mitochondria in T. cruzi. Important: the present proposal is linked to (and is complemmentary to) another similar to fund the visit of Prof. Wilfredo Quinones, and is aprt of a collaboration between our group and the group of Prof. Maria Júlia Manso Alves - Instituto de Química - Universidade de São Paulo). (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BARBOSA, ROSICLER L.; CHAGAS DA CUNHA, JULIA PINHEIRO; MENEZES, ARTHUR T.; MELO, RAISSA DE F. P.; ELIAS, MARIA CAROLINA; SILBER, ARIEL M.; COLTRI, PATRICIA P.. Proteomic analysis of Trypanosoma cruzi spliceosome complex. JOURNAL OF PROTEOMICS, v. 223, JUL 15 2020. (17/06994-9, 17/16553-0, 16/06034-2)

DAMASCENO, FLAVIA S.; BARISON, MARIA JULIA; CRISPIM, MARCELL; SOUZA, RODOLPHO O. O.; MARCHESE, LETICIA; SILBER, ARIEL M.. L-Glutamine uptake is developmentally regulated and is involved in metacyclogenesis in Trypanosoma cruzi. Molecular and Biochemical Parasitology, v. 224, p. 17-25, SEP 15 2018. (16/06034-2, 17/16553-0)

MARCHESE, LETICIA; NASCIMENTO, JANAINA DE FREITAS; DAMASCENO, FLAVIA SILVA; BRINGAUD, FREDERIC; MICHELS, PAUL A. M.; SILBER, ARIEL MARIANO. The Uptake and Metabolism of Amino Acids, and Their Unique Role in the Biology of Pathogenic Trypanosomatids. PATHOGENS, v. 7, n. 2, JUN 2018. (16/06034-2, 17/16553-0)

SOWERBY, KATE; FREITAG-POHL, STEFANIE; MURILLO, ANA MILENA; SILBER, ARIEL MARIANO; POHL, EHMKE. Cysteine synthase: multiple structures of a key enzyme in cysteine synthesis and a potential drug target for Chagas disease and leishmaniasis. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 79, p. 13-pg., 2023-06-01. (21/12938-0, 17/16553-0)

ROCHA, SANDRA CARLA; ROSA PEREZ, ANA; BELOSCAR, JUAN; BOTTASSO, OSCAR; SILBER, ARIEL MARIANO. Diminished Prolinemia in Chronic Chagasic Patients: A New Clue for Disease Pathology?. Molecules, v. 24, n. 17, SEP 1 2019. (16/06034-2, 17/16553-0)

DE ARAUJO, CHRISTIANE BEZERRA; DE LIMA, LOYZE PAOLA; CALDERANO, SIMONE GUEDES; DAMASCENO, FLAVIA SILVA; SILBER, ARIEL M.; ELIAS, MARIA CAROLINA. Pep5, a Fragment of Cyclin D2, Shows Antiparasitic Effects in Different Stages of the Trypanosoma cruzi Life Cycle and Blocks Parasite Infectivity. Antimicrobial Agents and Chemotherapy, v. 63, n. 5, MAY 2019. (13/07467-1, 16/06034-2, 17/16553-0, 16/50050-2, 14/13375-5)

GIRARD, RICHARD M. B. M.; CRISPIM, MARCELL; ALENCAR, MAYKE BEZERRA; SILBER, ARIEL MARIANO. Uptake of L-Alanine and Its Distinct Roles in the Bioenergetics of Trypanosoma cruzi. MSPHERE, v. 3, n. 4, JUL-AUG 2018. (16/06034-2, 17/16553-0)