Mitochondrial plasticity in Chagas disease.

Author(s)

Márcio Augusto Campos Ribeiro

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2022-03-04

Examining board members

Julio Cesar Batista Ferreira; Daniel Pedra Adesse; Igor Luchini Baptista; Gabriela Placoná Diniz

• Advisor: Julio Cesar Batista Ferreira

Abstract

Chagas disease (CD) which affects 8 million people worldwide, is caused by the protozoan Tryoanosoma cruzi. The parasitic infection caused by T. cruzi causes mitochondrial dysfunction in the host cell, both in the acute and chronic phases of the disease. Post infection, it is possible to observe an increase in mitochondrial size and density in the host cell. These changes follow the increase in parasite load and colocalization between parasite and host cell mitochondria. However, the real contribution of host cell mitochondria in the infection process, as well as in tissue degeneration caused by CD, has not yet been elucidated. Knowing that mitochondria is a dynamic organelle, capable of changing its number, size and density according to tissue metabolic demand, we hypothesized that both parasite infection and tissue degeneration resulting from infection dependence on the morphological and functional reorganization of the host cell mitochondria to meet the increased energy demand of the parasite. Furthermore, we propose that a modulation of these processes is capable of controlling and/or prevent progression of Chagas disease. Thus, the objective of the present proposal is to investigate the role of host cell mitochondrial plasticity in T. cruzi infection. Our results show that, in fact, the mitochondrial network of the host cell (fibroblast in culture) undergoes change in the face of infection with T. cruzi. We observed the appearance of mitochondrial aggregates close to the parasite and an increase in the levels of proteins related to mitochondrial fusion. Using knockout fibroblast for specific proteins involved in mitochondrial fission and fusion processes, we observed that the absence of the Opa1 protein (involved in mitochondrial inner membrane fusion and supercomplex formation) increases both the number of infected cells (parasitic load). The absence of the Opa1 protein also increases parasite evasion, suggesting an important role of this protein in the parasite invasion-differentiation-evasion process. However, Opa1 knockout cells show similar cell metabolism to wild-type cells 24h after infection, excluding the bioenergetic component in this Opa1-dependent phenotype. We also observed that fibroblast lacking Mfn1 (involved in mitochondrial outer membrane fusion) and Mff (involved in mitochondrial fission) have a reduced infection rate with no differences in differentiation and evasion. Our data point to an important role of mitochondrial dynamics in T. cruzi infection, since the absence of proteins related to mitochondrial fusion, specially Opa1, in host cell facilitated the parasite to complete its life cycle, and the absence of proteins related to mitochondrial fission made it difficult to the parasite to complete its life cycle. (AU)

• FAPESP's process: 18/00869-0 - Mitochondrial plasticity in Chagas Disease
• Grantee: Márcio Augusto Campos Ribeiro
• Support Opportunities: Scholarships in Brazil - Doctorate