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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2021
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oai:doaj.org-article:b43bed9146494db4a682bec71f6f2aff2021-11-11T12:11:56ZCo-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy1664-322410.3389/fimmu.2021.755862https://doaj.org/article/b43bed9146494db4a682bec71f6f2aff2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.755862/fullhttps://doaj.org/toc/1664-3224Infection 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.João Paulo Silva NunesJoão Paulo Silva NunesJoão Paulo Silva NunesJoão Paulo Silva NunesPauline AndrieuxPauline BrochetRafael Ribeiro AlmeidaRafael Ribeiro AlmeidaEduardo KitanoAndré Kenji HondaLeo Kei IwaiDébora Andrade-SilvaDavid GoudenègeKarla Deysiree Alcântara SilvaKarla Deysiree Alcântara SilvaRaquel de Souza VieiraDébora LevySergio Paulo BydlowskiFrédéric GallardoMagali TorresEdimar Alcides BocchiMiguel ManoRonaldo Honorato Barros SantosFernando BacalPablo PomerantzeffFrancisco Rafael Martins LaurindoPriscila Camillo TeixeiraHelder I. NakayaJorge KalilJorge KalilJorge KalilVincent ProcaccioChristophe ChevillardEdecio Cunha-NetoEdecio Cunha-NetoEdecio Cunha-NetoFrontiers Media S.A.articlemitochondrial dysfunctionchronic Chagas disease cardiomyopathyinterferon gammaenergy metabolismmitochondriaImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
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EN |
| topic |
mitochondrial dysfunction chronic Chagas disease cardiomyopathy interferon gamma energy metabolism mitochondria Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
mitochondrial dysfunction chronic Chagas disease cardiomyopathy interferon gamma energy metabolism mitochondria Immunologic diseases. Allergy RC581-607 João Paulo Silva Nunes João Paulo Silva Nunes João Paulo Silva Nunes João Paulo Silva Nunes Pauline Andrieux Pauline Brochet Rafael Ribeiro Almeida Rafael Ribeiro Almeida Eduardo Kitano André Kenji Honda Leo Kei Iwai Débora Andrade-Silva David Goudenège Karla Deysiree Alcântara Silva Karla Deysiree Alcântara Silva Raquel de Souza Vieira Débora Levy Sergio Paulo Bydlowski Frédéric Gallardo Magali Torres Edimar Alcides Bocchi Miguel Mano Ronaldo Honorato Barros Santos Fernando Bacal Pablo Pomerantzeff Francisco Rafael Martins Laurindo Priscila Camillo Teixeira Helder I. Nakaya Jorge Kalil Jorge Kalil Jorge Kalil Vincent Procaccio Christophe Chevillard Edecio Cunha-Neto Edecio Cunha-Neto Edecio Cunha-Neto 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 |
| 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. |
| format |
article |
| author |
João Paulo Silva Nunes João Paulo Silva Nunes João Paulo Silva Nunes João Paulo Silva Nunes Pauline Andrieux Pauline Brochet Rafael Ribeiro Almeida Rafael Ribeiro Almeida Eduardo Kitano André Kenji Honda Leo Kei Iwai Débora Andrade-Silva David Goudenège Karla Deysiree Alcântara Silva Karla Deysiree Alcântara Silva Raquel de Souza Vieira Débora Levy Sergio Paulo Bydlowski Frédéric Gallardo Magali Torres Edimar Alcides Bocchi Miguel Mano Ronaldo Honorato Barros Santos Fernando Bacal Pablo Pomerantzeff Francisco Rafael Martins Laurindo Priscila Camillo Teixeira Helder I. Nakaya Jorge Kalil Jorge Kalil Jorge Kalil Vincent Procaccio Christophe Chevillard Edecio Cunha-Neto Edecio Cunha-Neto Edecio Cunha-Neto |
| author_facet |
João Paulo Silva Nunes João Paulo Silva Nunes João Paulo Silva Nunes João Paulo Silva Nunes Pauline Andrieux Pauline Brochet Rafael Ribeiro Almeida Rafael Ribeiro Almeida Eduardo Kitano André Kenji Honda Leo Kei Iwai Débora Andrade-Silva David Goudenège Karla Deysiree Alcântara Silva Karla Deysiree Alcântara Silva Raquel de Souza Vieira Débora Levy Sergio Paulo Bydlowski Frédéric Gallardo Magali Torres Edimar Alcides Bocchi Miguel Mano Ronaldo Honorato Barros Santos Fernando Bacal Pablo Pomerantzeff Francisco Rafael Martins Laurindo Priscila Camillo Teixeira Helder I. Nakaya Jorge Kalil Jorge Kalil Jorge Kalil Vincent Procaccio Christophe Chevillard Edecio Cunha-Neto Edecio Cunha-Neto Edecio Cunha-Neto |
| author_sort |
João Paulo Silva Nunes |
| 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_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_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_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 |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/b43bed9146494db4a682bec71f6f2aff |
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