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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

Infection by the protozoan Trypanosoma cruzi causes Chagas disease cardiomyopathy (CCC) and can lead to arrhythmia, heart failure and death. Chagas disease affects 8 million people worldwide, and chronic production of the cytokines IFN-γ and TNF-α by T cells together with mitochondrial dysfunction a...

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Autores principales: Nunes, João Paulo Silva, Andrieux, Pauline, Brochet, Pauline, Almeida, Rafael Ribeiro, Kitano, Eduardo, Honda, André Kenji, Iwai, Leo Kei, Andrade-Silva, Débora, Goudenège, David, Alcântara Silva, Karla Deysiree, Vieira, Raquel de Souza, Levy, Débora, Bydlowski, Sergio Paulo, Gallardo, Frédéric, Torres, Magali, Bocchi, Edimar Alcides, Mano, Miguel, Santos, Ronaldo Honorato Barros, Bacal, Fernando, Pomerantzeff, Pablo, Laurindo, Francisco Rafael Martins, Teixeira, Priscila Camillo, Nakaya, Helder I., Kalil, Jorge, Procaccio, Vincent, Chevillard, Christophe, Cunha-Neto, Edecio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632642/
https://www.ncbi.nlm.nih.gov/pubmed/34867992
http://dx.doi.org/10.3389/fimmu.2021.755862
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author Nunes, João Paulo Silva
Andrieux, Pauline
Brochet, Pauline
Almeida, Rafael Ribeiro
Kitano, Eduardo
Honda, André Kenji
Iwai, Leo Kei
Andrade-Silva, Débora
Goudenège, David
Alcântara Silva, Karla Deysiree
Vieira, Raquel de Souza
Levy, Débora
Bydlowski, Sergio Paulo
Gallardo, Frédéric
Torres, Magali
Bocchi, Edimar Alcides
Mano, Miguel
Santos, Ronaldo Honorato Barros
Bacal, Fernando
Pomerantzeff, Pablo
Laurindo, Francisco Rafael Martins
Teixeira, Priscila Camillo
Nakaya, Helder I.
Kalil, Jorge
Procaccio, Vincent
Chevillard, Christophe
Cunha-Neto, Edecio
author_facet Nunes, João Paulo Silva
Andrieux, Pauline
Brochet, Pauline
Almeida, Rafael Ribeiro
Kitano, Eduardo
Honda, André Kenji
Iwai, Leo Kei
Andrade-Silva, Débora
Goudenège, David
Alcântara Silva, Karla Deysiree
Vieira, Raquel de Souza
Levy, Débora
Bydlowski, Sergio Paulo
Gallardo, Frédéric
Torres, Magali
Bocchi, Edimar Alcides
Mano, Miguel
Santos, Ronaldo Honorato Barros
Bacal, Fernando
Pomerantzeff, Pablo
Laurindo, Francisco Rafael Martins
Teixeira, Priscila Camillo
Nakaya, Helder I.
Kalil, Jorge
Procaccio, Vincent
Chevillard, Christophe
Cunha-Neto, Edecio
author_sort Nunes, João Paulo Silva
collection PubMed
description Infection by the protozoan Trypanosoma cruzi causes Chagas disease cardiomyopathy (CCC) and can lead to arrhythmia, heart failure and death. Chagas disease affects 8 million people worldwide, and chronic production of the cytokines IFN-γ and TNF-α by T cells together with mitochondrial dysfunction are important players for the poor prognosis of the disease. Mitochondria occupy 40% of the cardiomyocytes volume and produce 95% of cellular ATP that sustain the life-long cycles of heart contraction. As IFN-γ and TNF-α have been described to affect mitochondrial function, we hypothesized that IFN-γ and TNF-α are involved in the myocardial mitochondrial dysfunction observed in CCC patients. In this study, we quantified markers of mitochondrial dysfunction and nitro-oxidative stress in CCC heart tissue and in IFN-γ/TNF-α-stimulated AC-16 human cardiomyocytes. We found that CCC myocardium displayed increased levels of nitro-oxidative stress and reduced mitochondrial DNA as compared with myocardial tissue from patients with dilated cardiomyopathy (DCM). IFN-γ/TNF-α treatment of AC-16 cardiomyocytes induced increased nitro-oxidative stress and decreased the mitochondrial membrane potential (ΔΨm). We found that the STAT1/NF-κB/NOS2 axis is involved in the IFN-γ/TNF-α-induced decrease of ΔΨm in AC-16 cardiomyocytes. Furthermore, treatment with mitochondria-sparing agonists of AMPK, NRF2 and SIRT1 rescues ΔΨm in IFN-γ/TNF-α-stimulated cells. Proteomic and gene expression analyses revealed that IFN-γ/TNF-α-treated cells corroborate mitochondrial dysfunction, transmembrane potential of mitochondria, altered fatty acid metabolism and cardiac necrosis/cell death. Functional assays conducted on Seahorse respirometer showed that cytokine-stimulated cells display decreased glycolytic and mitochondrial ATP production, dependency of fatty acid oxidation as well as increased proton leak and non-mitochondrial oxygen consumption. Together, our results suggest that IFN-γ and TNF-α cause direct damage to cardiomyocytes’ mitochondria by promoting oxidative and nitrosative stress and impairing energy production pathways. We hypothesize that treatment with agonists of AMPK, NRF2 and SIRT1 might be an approach to ameliorate the progression of Chagas disease cardiomyopathy.
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spelling pubmed-86326422021-12-02 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 Nunes, João Paulo Silva Andrieux, Pauline Brochet, Pauline Almeida, Rafael Ribeiro Kitano, Eduardo Honda, André Kenji Iwai, Leo Kei Andrade-Silva, Débora Goudenège, David Alcântara Silva, Karla Deysiree Vieira, Raquel de Souza Levy, Débora Bydlowski, Sergio Paulo Gallardo, Frédéric Torres, Magali Bocchi, Edimar Alcides Mano, Miguel Santos, Ronaldo Honorato Barros Bacal, Fernando Pomerantzeff, Pablo Laurindo, Francisco Rafael Martins Teixeira, Priscila Camillo Nakaya, Helder I. Kalil, Jorge Procaccio, Vincent Chevillard, Christophe Cunha-Neto, Edecio Front Immunol Immunology Infection by the protozoan Trypanosoma cruzi causes Chagas disease cardiomyopathy (CCC) and can lead to arrhythmia, heart failure and death. Chagas disease affects 8 million people worldwide, and chronic production of the cytokines IFN-γ and TNF-α by T cells together with mitochondrial dysfunction are important players for the poor prognosis of the disease. Mitochondria occupy 40% of the cardiomyocytes volume and produce 95% of cellular ATP that sustain the life-long cycles of heart contraction. As IFN-γ and TNF-α have been described to affect mitochondrial function, we hypothesized that IFN-γ and TNF-α are involved in the myocardial mitochondrial dysfunction observed in CCC patients. In this study, we quantified markers of mitochondrial dysfunction and nitro-oxidative stress in CCC heart tissue and in IFN-γ/TNF-α-stimulated AC-16 human cardiomyocytes. We found that CCC myocardium displayed increased levels of nitro-oxidative stress and reduced mitochondrial DNA as compared with myocardial tissue from patients with dilated cardiomyopathy (DCM). IFN-γ/TNF-α treatment of AC-16 cardiomyocytes induced increased nitro-oxidative stress and decreased the mitochondrial membrane potential (ΔΨm). We found that the STAT1/NF-κB/NOS2 axis is involved in the IFN-γ/TNF-α-induced decrease of ΔΨm in AC-16 cardiomyocytes. Furthermore, treatment with mitochondria-sparing agonists of AMPK, NRF2 and SIRT1 rescues ΔΨm in IFN-γ/TNF-α-stimulated cells. Proteomic and gene expression analyses revealed that IFN-γ/TNF-α-treated cells corroborate mitochondrial dysfunction, transmembrane potential of mitochondria, altered fatty acid metabolism and cardiac necrosis/cell death. Functional assays conducted on Seahorse respirometer showed that cytokine-stimulated cells display decreased glycolytic and mitochondrial ATP production, dependency of fatty acid oxidation as well as increased proton leak and non-mitochondrial oxygen consumption. Together, our results suggest that IFN-γ and TNF-α cause direct damage to cardiomyocytes’ mitochondria by promoting oxidative and nitrosative stress and impairing energy production pathways. We hypothesize that treatment with agonists of AMPK, NRF2 and SIRT1 might be an approach to ameliorate the progression of Chagas disease cardiomyopathy. Frontiers Media S.A. 2021-11-11 /pmc/articles/PMC8632642/ /pubmed/34867992 http://dx.doi.org/10.3389/fimmu.2021.755862 Text en Copyright © 2021 Nunes, Andrieux, Brochet, Almeida, Kitano, Honda, Iwai, Andrade-Silva, Goudenège, Alcântara Silva, Vieira, Levy, Bydlowski, Gallardo, Torres, Bocchi, Mano, Santos, Bacal, Pomerantzeff, Laurindo, Teixeira, Nakaya, Kalil, Procaccio, Chevillard and Cunha-Neto https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Nunes, João Paulo Silva
Andrieux, Pauline
Brochet, Pauline
Almeida, Rafael Ribeiro
Kitano, Eduardo
Honda, André Kenji
Iwai, Leo Kei
Andrade-Silva, Débora
Goudenège, David
Alcântara Silva, Karla Deysiree
Vieira, Raquel de Souza
Levy, Débora
Bydlowski, Sergio Paulo
Gallardo, Frédéric
Torres, Magali
Bocchi, Edimar Alcides
Mano, Miguel
Santos, Ronaldo Honorato Barros
Bacal, Fernando
Pomerantzeff, Pablo
Laurindo, Francisco Rafael Martins
Teixeira, Priscila Camillo
Nakaya, Helder I.
Kalil, Jorge
Procaccio, Vincent
Chevillard, Christophe
Cunha-Neto, Edecio
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632642/
https://www.ncbi.nlm.nih.gov/pubmed/34867992
http://dx.doi.org/10.3389/fimmu.2021.755862
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