Figure 8.

Proposed model for the mitochondrial dysfunction in Chagas disease cardiomyopathy. Left panel: in summary, our results showed that heart tissues from CCC patients have increased production of RNS and reduced content of mitochondrial DNA in comparison with patients with DCM. Similarly, stimulation of AC-16 cardiomyocytes with IFN-γ/TNF-α increased ROS, RNS and proton leak, impaired ΔΨm, depleted ATP production and changed the metabolic profile of the cells. Right panel: in our rescue model, we showed that pharmacological inhibition of molecules involved in the IFN-γ/TNF-α/NF-κB/NOS2 pathway ameliorated the ΔΨm and NO production. Additionally, activation of AMPK/SIRT1 and NRF2 had beneficial impact on the ΔΨm. Thus, we hypothesize that mitochondrial dysfunction is driven by the excessive production of IFN-γ/TNF-α in CCC myocardium and is an essential component for the poor prognosis of Chagas disease cardiomyopathy. Mitochondria-targeted therapies might improve CCC disease progression. Compounds in yellow are inhibitors; Compounds in light green are agonists. Connecting arrows indicate activation and flat line means inhibitory interaction. Red and green arrows indicate the changes observed before and after treatment with the compounds.