The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

Figure 1

A mechanism to explain the mitochondrial dysfunction in Chagas disease. NOX2 is activated in T. cruzi-infected monocytes and macrophages, which can produce ROS. On the other hand, T. cruzi infection can induce an intracellular calcium flux (iCa²⁺), which in turn causes mitochondrial membrane permeability, respiratory complex malfunction, and electron leakage from the electron transport chain to oxygen, which results in increased mtROS production. Most likely, the iCa²⁺ is associated with changes in the inositol 1,4,5 trisphosphate (IP3) signaling pathway, which can cause Ca²⁺ release from the sarcoplasmic reticulum and the nuclear envelope. Both NOX2-produced ROS and mtROS can inhibit the activity of the transcriptional coactivator PGC-1α, a coactivator of NRF1, NRF2, and other transcription factors (TF) involved in mitochondrial biogenesis, OXPHOS, mtDNA replication, and transcription, altering the redox homeostasis of the mitochondria. Additionally, ROS could directly inhibit the activity of NRF1 and NRF2, leading to mitochondrial dysfunction as well. +1 represents the transcription start site of the genes.