Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease

Ouarhache, Maryem; Marquet, Sandrine; Frade, Amanda Farage; Ferreira, Ariela Mota; Ianni, Bárbara Maria; Almeida, Rafael Ribeiro; Nunes, João Paulo Silva; Ferreira, Ludmila Rodrigues Pinto; Rigaud, Vagner Oliveira Carvalho; Cândido, Darlan da Silva; Mady, Charles; Zaniratto, Ricardo Costa Fernandes; Buck, Paula; Torres, Magali; Gallardo, Frédéric; Andrieux, Pauline; Bydlowsky, Sergio; Levy, Débora; Abel, Laurent; Cardoso, Clareci Silva; Santos-Junior, Omar R; Oliveira, Léa Campos de; Oliveira, Cláudia Di Lorenzo; Nunes, Maria do Carmo Pereira; Cobat, Aurélie; Kalil, Jorge; Ribeiro, Antônio Luiz Pinho; Sabino, Éster Cerdeira; Cunha‐Neto, Edécio; Chevillard, Christophe

doi:10.1007/s10875-021-01000-y

Cited by 20 publications

(29 citation statements)

References 48 publications

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“…Decreased in vivo ATP production was also observed in the CCC myocardium ( 21 ). In addition, our group identified an accumulation of heterozygous pathogenic variations including loss-of-function and stopgain/truncation of key mitochondrial genes in CCC patients ( 62 ). The loss of function mutation in one of the studied families was dihydroorotate dehydrogenase (DHODH) R135C.…”

Section: Discussionmentioning

confidence: 99%

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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

et al. 2021

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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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Section: Discussionmentioning

confidence: 99%

“…The loss of function mutation in one of the studied families was dihydroorotate dehydrogenase (DHODH) R135C. DHODH is involved in the oxidative phosphorylation by donating electrons to complex III and treatment with DHODH inhibitor Brequinar in IFN-γ+TNF-α-treated AC-16 cardiomyocytes caused additive damage to mitochondrial ΔΨm ( 62 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Decreased mitochondrial rRNA (15), rDNA (54) and in vivo ATP production (24) were observed in CCC myocardium. The IFN-gamma-producing Tcell rich inflammatory profile is a major difference between CCC and DCM; indeed, IFN-gamma is the most highly expressed cytokine in CCC heart tissue (14,(17)(18)(19)55) and the top upstream gene regulator upon pathways analysis in CCC myocardium (20). It is known that IFN-gamma has multiple deleterious effects on cardiomyocyte mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Impairment of Multiple Mitochondrial Energy Metabolism Pathways in the Heart of Chagas Disease Cardiomyopathy Patients

et al. 2021

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Chagas disease cardiomyopathy (CCC) is an inflammatory dilated cardiomyopathy occurring in 30% of the 6 million infected with the protozoan Trypanosoma cruzi in Latin America. Survival is significantly lower in CCC than ischemic (IC) and idiopathic dilated cardiomyopathy (DCM). Previous studies disclosed a selective decrease in mitochondrial ATP synthase alpha expression and creatine kinase activity in CCC myocardium as compared to IDC and IC, as well as decreased in vivo myocardial ATP production. Aiming to identify additional constraints in energy metabolism specific to CCC, we performed a proteomic study in myocardial tissue samples from CCC, IC and DCM obtained at transplantation, in comparison with control myocardial tissue samples from organ donors. Left ventricle free wall myocardial samples were subject to two-dimensional electrophoresis with fluorescent labeling (2D-DIGE) and protein identification by mass spectrometry. We found altered expression of proteins related to mitochondrial energy metabolism, cardiac remodeling, and oxidative stress in the 3 patient groups. Pathways analysis of proteins differentially expressed in CCC disclosed mitochondrial dysfunction, fatty acid metabolism and transmembrane potential of mitochondria. CCC patients’ myocardium displayed reduced expression of 22 mitochondrial proteins belonging to energy metabolism pathways, as compared to 17 in DCM and 3 in IC. Significantly, 6 beta-oxidation enzymes were reduced in CCC, while only 2 of them were down-regulated in DCM and 1 in IC. We also observed that the cytokine IFN-gamma, previously described with increased levels in CCC, reduces mitochondrial membrane potential in cardiomyocytes. Results suggest a major reduction of mitochondrial energy metabolism and mitochondrial dysfunction in CCC myocardium which may be in part linked to IFN-gamma. This may partially explain the worse prognosis of CCC as compared to DCM or IC.

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“…Very little is known about the genetic contribution to the progression of chronic inflammatory cardiomyopathy in chronic Chagas disease and the factors that increase cardiomyocyte susceptibility to inflammatory damage. A recent and interesting exome sequencing analysis was performed to study nuclear families containing multiple cases with chronic Chagas inflammatory cardiomyopathy and chronic-infected asymptomatic siblings and in unrelated but infected asymptomatic individuals [ 97 ]. Heterozygous pathogenic variants are linked to chronic Chagas disease in all tested families on twenty-two distinct genes; twenty were mitochondrial or inflammation-related, with most of them involved in proinflammatory cytokine production [ 97 ].…”

Section: Genetic Variants Associated With Mitochondrial Dysfunction and Inflammation In Cardiomyopathies In Chagas Diseasementioning

confidence: 99%

The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

Maldonado

Rojas

Urbina

et al. 2021

Oxidative Medicine and Cellular Longevity

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Chagas disease is a neglected tropical disease caused by the flagellated protozoa Trypanosoma cruzi that affects several million people mainly in Latin American countries. Chagas disease has two phases, which are acute and chronic, both separated by an indeterminate time period in which the infected individual is relatively asymptomatic. The acute phase extends for 40-60 days with atypical and mild symptoms; however, about 30% of the infected patients will develop a symptomatic chronic phase, which is characterized by either cardiac, digestive, neurological, or endocrine problems. Cardiomyopathy is the most important and severe result of Chagas disease, which leads to left ventricular systolic dysfunction, heart failure, and sudden cardiac death. Most deaths are due to heart failure (70%) and sudden death (30%) resulting from cardiomyopathy. During the chronic phase, T. cruzi-infected macrophages respond with the production of proinflammatory cytokines and production of superoxide and nitric oxide by the NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) enzymes, respectively. During the chronic phase, myocardial changes are produced as a result of chronic inflammation, oxidative stress, fibrosis, and cell death. The cellular inflammatory response is mainly the result of activation of the NF-κB-dependent pathway, which activates gene expression of inflammatory cytokines, leading to progressive tissue damage. The persisting production of reactive oxygen species (ROS) is the result of mitochondrial dysfunction in the cardiomyocytes. In this review, we will discuss inflammation and oxidative damage which is produced in the heart during the chronic phase of Chagas disease and recent evidence on the role of macrophages and the production of proinflammatory cytokines during the acute phase and the origin of macrophages/monocytes during the chronic phase of Chagas disease. We will also discuss the contributing factors and mechanisms leading to the chronic inflammation of the cardiac tissue during the chronic phase of the disease as well as the innate and adaptive host immune response. The contribution of genetic factors to the progression of the chronic inflammatory cardiomyopathy of chronic Chagas disease is also discussed. The secreted extracellular vesicles (exosomes) produced for both T. cruzi and infected host cells can play key roles in the host immune response, and those roles are described. Lastly, we describe potential treatments to attenuate the chronic inflammation of the cardiac tissue, designed to improve heart function in chagasic patients.

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Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease

Cited by 20 publications

References 48 publications

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

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

Impairment of Multiple Mitochondrial Energy Metabolism Pathways in the Heart of Chagas Disease Cardiomyopathy Patients

The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

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