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

Abstract

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.

T-Cell Subpopulations Exhibit Distinct Recruitment Potential, Immunoregulatory Profile and Functional Characteristics in Chagas versus Idiopathic Dilated Cardiomyopathies

“…KEGG enrichment analyses identified inflammatory pathways as the main ones amongst the first 20 pathways with lowest FDR, of particular interest, the T-cell signaling and the TNF signaling pathways. These data corroborate previous studies that highlight the role of inflammatory molecules in the immunopathology of Chagas disease (54)(55)(56). Exploiting the molecules that compose these pathways may provide potential targets to treat CCC.…”

Sex Differences in Cardiac Pathology of SARS-CoV2 Infected and Trypanosoma cruzi Co-infected Mice

“…CD has been tightly linked to alterations in metabolic substrate utilization and impairments of mitochondrial oxidative capacity and endoplasmic reticulum functions in the hearts (22,33,(66)(67)(68). It is known that patients with heart disease exhibit a shift from fatty acid oxidation toward greater dependance on glucose as a source for cellular energy adenosine triphosphate (ATP) (69).…”

“…It is known that patients with heart disease exhibit a shift from fatty acid oxidation toward greater dependance on glucose as a source for cellular energy adenosine triphosphate (ATP) ( 69 ). Thus, mitochondria have become a key target in combating this metabolic reprogramming in heart disease including CD ( 66 ). Exhaustion of mitochondria or increased mitochondrial oxidative stress results in mutations in mitochondrial DNA, mitochondrial dysfunction and oxidative stress causing cachexia, cardiac atrophy and heart failure ( 70 ).…”

Surfaceome mapping of primary human heart cells with CellSurfer uncovers cardiomyocyte surface protein LSMEM2 and proteome dynamics in failing hearts

“…This could explain why changes for LSMEM2 and other proteins highlighted in Fig. 8e,f have not been reported in three previous generic proteomic analyses of heart failure that used homogenized human tissue [44][45][46] . Thus, measuring low-abundance cell surface proteins in isolated cells, as done here with CellSurfer, is critical for developing an accurate understanding of the protein events that occur in heart disease.…”