Inflammation and mitochondria in the pathogenesis of chronic Chagas disease cardiomyopathy

Autor(es)

Nunes, Joao Paulo Silva ; Roda, Vinicius Moraes de Paiva ; Andrieux, Pauline ; Kalil, Jorge ; Chevillard, Christophe ; Cunha-Neto, Edecio

• Tipo de documento: Artigo Científico
• Fonte: Experimental Biology and Medicine; v. 248, n. 22, p. 10-pg., 2024-01-18.

Resumo

Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, is a neglected disease affecting around 6 million people. About 30% of CD patients develop chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy that occurs decades after the initial infection, while most infected patients (60%) remain asymptomatic in the so-called indeterminate form (IF). Death results from heart failure or arrhythmia in a subset of CCC patients. Myocardial fibrosis, inflammation, and mitochondrial dysfunction are involved in the arrhythmia substrate and triggering events. Survival in CCC is worse than in other cardiomyopathies, which may be linked to a Th1-T cell rich myocarditis with abundant interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, selectively lower levels of mitochondrial energy metabolism enzymes in the heart, and reduced levels of high-energy phosphate, indicating poor adenosine triphosphate (ATP) production. IFN-gamma and TNF-alpha signaling, which are constitutively upregulated in CD patients, negatively affect mitochondrial function in cardiomyocytes, recapitulating findings in CCC heart tissue. Genetic studies such as whole-exome sequencing (WES) in nuclear families with multiple CCC/IF cases has disclosed rare heterozygous pathogenic variants in mitochondrial and inflammatory genes segregating in CCC cases. In this minireview, we summarized studies showing how IFN-gamma and TNF-alpha affect cell energy generation, mitochondrial health, and redox homeostasis in cardiomyocytes, in addition to human CD and mitochondria. We hypothesize that cytokine-induced mitochondrial dysfunction in genetically predisposed patients may be the underlying cause of CCC severity and we believe this mechanism may have a bearing on other inflammatory cardiomyopathies. (AU)

• Processo FAPESP: 22/00758-0 - Mitocôndrias, interferon gama e genética na cardiopatia chagásica crônica: patogenia, alvos terapêuticos e marcadores prognósticos
• Beneficiário: Edecio Cunha Neto
• Modalidade de apoio: Auxílio à Pesquisa - Temático