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

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Nunes, Joao Paulo Silva ^{[1, 2, 3, 4]} ; Andrieux, Pauline ^[4] ; Brochet, Pauline ^[4] ; Almeida, Rafael Ribeiro ^{[2, 3]} ; Kitano, Eduardo ^[2] ; Honda, Andre Kenji ^[2] ; Iwai, Leo Kei ^[5] ; Andrade-Silva, Debora ^[5] ; Goudenege, David ^[6] ; Alcantara Silva, Karla Deysiree ^{[1, 2]} ; Vieira, Raquel de Souza ^[2] ; Levy, Debora ^[2] ; Bydlowski, Sergio Paulo ^[2] ; Gallardo, Frederic ^[4] ; Torres, Magali ^[4] ; Bocchi, Edimar Alcides ^[7] ; Mano, Miguel ^[8] ; Santos, Ronaldo Honorato Barros ^[9] ; Bacal, Fernando ^[9] ; Pomerantzeff, Pablo ^[9] ; Laurindo, Francisco Rafael Martins ^[10] ; Teixeira, Priscila Camillo ^[11] ; Nakaya, Helder I. ^[12] ; Kalil, Jorge ^{[1, 2, 3]} ; Procaccio, Vincent ^[13] ; Chevillard, Christophe ^[4] ; Cunha-Neto, Edecio ^{[1, 2, 3]}

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^[1] Univ Sao Paulo, Fac Med, Div Clin Immunol & Allergy, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Hosp Clin, Lab Immunol, Heart Inst Incor, Sao Paulo - Brazil

^[3] Inst Nacl Ciencia & Tecnol, Inst Invest Immunol, Sao Paulo - Brazil

^[4] Aix Marseille Univ, TAGC, Inst MarMaRa, INSERM, UMR 1090, Marseille - France

^[5] Inst Butantan, Lab Especial Toxinol Aplicada, Ctr Toxins Immune Response & Cell Signaling CeTIC, Sao Paulo - Brazil

^[6] Univ Hosp Angers, Dept Biochem & Genet, Angers - France

^[7] Univ Sao Paulo, Fac Med, Heart Inst Incor Hosp Clin, Heart Failure Team, Sao Paulo - Brazil

^[8] Univ Coimbra, Ctr Neurosci & Cell Biol CNC, Funct Genom & RNA Based Therapeut Lab, Coimbra - Portugal

^[9] Univ Sao Paulo, Inst Heart, Sch Med, Div Surg, Sao Paulo - Brazil

^[10] Univ Sao Paulo, Inst Heart, Sch Med, Lab Vasc Biol, Sao Paulo - Brazil

^[11] F Hoffmann La Roche, Translat Res Sci, Pharma Res & Early Dev, Basel - Switzerland

^[12] Hosp Israelita Albert Einstein, Sao Paulo - Brazil

^[13] Univ Angers, MitoLab, UMR CNRS 6015, INSERM U1083, Angers - France

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN IMMUNOLOGY; v. 12, NOV 11 2021.
• Citações Web of Science: 0

Resumo

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-gamma and TNF-alpha 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-gamma and TNF-alpha have been described to affect mitochondrial function, we hypothesized that IFN-gamma and TNF-alpha 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-gamma/TNF-alpha-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-gamma/TNF-alpha treatment of AC-16 cardiomyocytes induced increased nitro-oxidative stress and decreased the mitochondrial membrane potential (Delta psi m). We found that the STAT1/NF-kappa B/NOS2 axis is involved in the IFN-gamma/TNF-alpha-induced decrease of Delta psi m in AC-16 cardiomyocytes. Furthermore, treatment with mitochondria-sparing agonists of AMPK, NRF2 and SIRT1 rescues Delta psi m in IFN-gamma/TNF-alpha-stimulated cells. Proteomic and gene expression analyses revealed that IFN-gamma/TNF-alpha-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-gamma and TNF-alpha 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. (AU)

• Processo FAPESP: 14/50890-5 - INCT 2014: Investigação em Imunologia
• Beneficiário: Jorge Elias Kalil Filho
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/50302-3 - Identificação de uma assinatura genética preditiva / prognóstica na Doença de Chagas: abordagem de biologia de sistemas
• Beneficiário: Edecio Cunha Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular