Key result
Trypanosoma cruzi infection in human cardiomyocytes and chagasic hearts severely compromised mtDNA replication, resulting in a decrease of mtDNA replication by 83% and mtDNA content by 40% to 65%.
Observational
Trypanosoma cruzi infection impairs mtDNA replication and OXPHOS gene expression in human cardiomyocytes, driven by increased ROS and compromised NRF2-mediated antioxidant responses.
Implicates mitochondrial dysfunction in Chagas cardiomyopathy; leaves open whether targeting mtDNA replication or NRF2 alters progression.
BACKGROUND: Mitochondrial dysfunction is a key determinant in chagasic cardiomyopathy development in mice; however, its relevance in human Chagas disease is not known. We determined if defects in mitochondrial biogenesis and dysregulation of peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 (PGC-1)-regulated transcriptional pathways constitute a mechanism or mechanisms underlying mitochondrial oxidative-phosphorylation (OXPHOS) deficiency in human Chagas disease. METHODS AND RESULTS: We utilized human cardiomyocytes and left-ventricular tissue from chagasic and other cardiomyopathy patients and healthy donors (n>6/group). We noted no change in citrate synthase activity, yet mRNA and/or protein levels of subunits of the respiratory complexes were significantly decreased in Trypanosoma cruzi-infected cardiomyocytes (0 to 24 hours) and chagasic hearts. We observed increased mRNA and decreased nuclear localization of PGC-1-coactivated transcription factors, yet the expression of genes for PPARγ-regulated fatty acid oxidation and nuclear respiratory factor (NRF1/2)-regulated mtDNA replication and transcription machinery was enhanced in infected cardiomyocytes and chagasic hearts. The D-loop formation was normal or higher, but mtDNA replication and mtDNA content were decreased by 83% and 40% to 65%, respectively. Subsequently, we noted that reactive oxygen species (ROS), oxidative stress, and mtDNA oxidation were significantly increased, yet NRF1/2-regulated antioxidant gene expression remained compromised in infected cardiomyocytes and chagasic hearts. CONCLUSIONS: The replication of mtDNA was severely compromised, resulting in a significant loss of mtDNA and expression of OXPHOS genes in T cruzi-infected cardiomyocytes and chagasic hearts. Our data suggest increased ROS generation and selective functional incapacity of NRF2-mediated antioxidant gene expression played a role in the defects in mtDNA replication and unfitness of mtDNA for replication and gene expression in Chagas disease.
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Wan et al. (2012) conducted an observational in Chagas disease. Trypanosoma cruzi infection vs. Healthy donors and uninfected cardiomyocytes was evaluated on mtDNA replication and mtDNA content. Trypanosoma cruzi infection in human cardiomyocytes and chagasic hearts severely compromised mtDNA replication, resulting in a decrease of mtDNA replication by 83% and mtDNA content by 40% to 65%.
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