Co-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy

• DOI: 10.3389/fimmu.2021.755862
• Publication Date: 2021-11-11T12:12:06Z
• Authors: João Paulo Silva ...; Pauline Andrieux; Pauline Brochet; Rafael Ribeiro Al...; Eduardo Kitano; André Kenji Honda; Leo Kei Iwai; Débora Andrade-Silva; David Goudenège; Karla Deysiree Al...; Raquel de Souza V...; Débora Levy; Sergio Paulo Bydl...; Frédéric Gallardo; Magali Torres; Edimar Alcides Bo...; Miguel Mano; Ronaldo Honorato ...; Fernando Bacal; Pablo Pomerantzeff; Francisco Rafael ...; Priscila Camillo ...; Helder I. Nakaya; Jorge Kalil; Vincent Procaccio; Christophe Chevil...; Edecio Cunha-Neto
• Keywords: Dilated Cardiomyopathy

Infection by the protozoan Trypanosoma cruzi causes Chagas disease cardiomyopathy (CCC) and can lead to arrhythmia, heart failure death. affects 8 million people worldwide, chronic production of cytokines IFN-γ TNF-α T cells together with mitochondrial dysfunction are important players for poor prognosis disease. Mitochondria occupy 40% cardiomyocytes volume produce 95% cellular ATP that sustain life-long cycles contraction. As have been described affect function, we hypothesized involved in myocardial observed CCC patients. In this study, quantified markers nitro-oxidative stress tissue IFN-γ/TNF-α-stimulated AC-16 human cardiomyocytes. We found myocardium displayed increased levels reduced DNA as compared from patients dilated (DCM). IFN-γ/TNF-α treatment induced decreased membrane potential (ΔΨm). STAT1/NF-κB/NOS2 axis is IFN-γ/TNF-α-induced decrease ΔΨm Furthermore, mitochondria-sparing agonists AMPK, NRF2 SIRT1 rescues cells. Proteomic gene expression analyses revealed IFN-γ/TNF-α-treated corroborate dysfunction, transmembrane mitochondria, altered fatty acid metabolism cardiac necrosis/cell Functional assays conducted on Seahorse respirometer showed cytokine-stimulated display glycolytic production, dependency oxidation well proton leak non-mitochondrial oxygen consumption. Together, our results suggest cause direct damage cardiomyocytes’ mitochondria promoting oxidative nitrosative impairing energy pathways. hypothesize might be an approach ameliorate progression cardiomyopathy.