Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant...
- Autores
- Wan, Xianxiu; Gupta, Shivali; Zago, María Paola; Davidson, Mercy M.; Dousset, Pierre; Amoroso, Alejandro; Garg, Nisha Jain
- Año de publicación
- 2012
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- 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. 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. 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.
Fil: Wan, Xianxiu. University of Texas Medical Branch; Estados Unidos
Fil: Gupta, Shivali. University of Texas Medical Branch; Estados Unidos
Fil: Zago, María Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina
Fil: Davidson, Mercy M.. Columbia University; Estados Unidos
Fil: Dousset, Pierre. Hospital San Bernardo; Argentina
Fil: Amoroso, Alejandro. Hospital San Bernardo; Argentina
Fil: Garg, Nisha Jain. University of Texas Medical Branch; Estados Unidos - Materia
-
Chagas disease
Mitochondrial biogenesis
mtDNA replication
nNRF2
Oxidative stress
PGC-1α
Trypanosoma cruzi - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/24332
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Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant responseWan, XianxiuGupta, ShivaliZago, María PaolaDavidson, Mercy M.Dousset, PierreAmoroso, AlejandroGarg, Nisha JainChagas diseaseMitochondrial biogenesismtDNA replicationnNRF2Oxidative stressPGC-1αTrypanosoma cruzihttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Mitochondrial 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. 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. 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.Fil: Wan, Xianxiu. University of Texas Medical Branch; Estados UnidosFil: Gupta, Shivali. University of Texas Medical Branch; Estados UnidosFil: Zago, María Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; ArgentinaFil: Davidson, Mercy M.. Columbia University; Estados UnidosFil: Dousset, Pierre. Hospital San Bernardo; ArgentinaFil: Amoroso, Alejandro. Hospital San Bernardo; ArgentinaFil: Garg, Nisha Jain. University of Texas Medical Branch; Estados UnidosAmerican Heart Association2012-11-29info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/24332Wan, Xianxiu; Gupta, Shivali; Zago, María Paola; Davidson, Mercy M.; Dousset, Pierre; et al.; Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response; American Heart Association; Journal of the American Heart Association; 1; 6; 29-11-2012; 1-142047-9980CONICET DigitalCONICETenginfo:eu-repo/semantics/reference/url/http://jaha.ahajournals.org/content/1/6/e003855info:eu-repo/semantics/altIdentifier/url/http://jaha.ahajournals.org/content/1/6/e003855info:eu-repo/semantics/altIdentifier/doi/10.1161/JAHA.112.003855info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:47:13Zoai:ri.conicet.gov.ar:11336/24332instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:47:13.866CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response |
title |
Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response |
spellingShingle |
Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response Wan, Xianxiu Chagas disease Mitochondrial biogenesis mtDNA replication nNRF2 Oxidative stress PGC-1α Trypanosoma cruzi |
title_short |
Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response |
title_full |
Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response |
title_fullStr |
Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response |
title_full_unstemmed |
Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response |
title_sort |
Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response |
dc.creator.none.fl_str_mv |
Wan, Xianxiu Gupta, Shivali Zago, María Paola Davidson, Mercy M. Dousset, Pierre Amoroso, Alejandro Garg, Nisha Jain |
author |
Wan, Xianxiu |
author_facet |
Wan, Xianxiu Gupta, Shivali Zago, María Paola Davidson, Mercy M. Dousset, Pierre Amoroso, Alejandro Garg, Nisha Jain |
author_role |
author |
author2 |
Gupta, Shivali Zago, María Paola Davidson, Mercy M. Dousset, Pierre Amoroso, Alejandro Garg, Nisha Jain |
author2_role |
author author author author author author |
dc.subject.none.fl_str_mv |
Chagas disease Mitochondrial biogenesis mtDNA replication nNRF2 Oxidative stress PGC-1α Trypanosoma cruzi |
topic |
Chagas disease Mitochondrial biogenesis mtDNA replication nNRF2 Oxidative stress PGC-1α Trypanosoma cruzi |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
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. 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. 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. Fil: Wan, Xianxiu. University of Texas Medical Branch; Estados Unidos Fil: Gupta, Shivali. University of Texas Medical Branch; Estados Unidos Fil: Zago, María Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina Fil: Davidson, Mercy M.. Columbia University; Estados Unidos Fil: Dousset, Pierre. Hospital San Bernardo; Argentina Fil: Amoroso, Alejandro. Hospital San Bernardo; Argentina Fil: Garg, Nisha Jain. University of Texas Medical Branch; Estados Unidos |
description |
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. 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. 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. |
publishDate |
2012 |
dc.date.none.fl_str_mv |
2012-11-29 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/24332 Wan, Xianxiu; Gupta, Shivali; Zago, María Paola; Davidson, Mercy M.; Dousset, Pierre; et al.; Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response; American Heart Association; Journal of the American Heart Association; 1; 6; 29-11-2012; 1-14 2047-9980 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/24332 |
identifier_str_mv |
Wan, Xianxiu; Gupta, Shivali; Zago, María Paola; Davidson, Mercy M.; Dousset, Pierre; et al.; Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma cruzi infection in human cardiomyocytes and Chagasic patients: The role of Nrf1/2 and antioxidant response; American Heart Association; Journal of the American Heart Association; 1; 6; 29-11-2012; 1-14 2047-9980 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/reference/url/http://jaha.ahajournals.org/content/1/6/e003855 info:eu-repo/semantics/altIdentifier/url/http://jaha.ahajournals.org/content/1/6/e003855 info:eu-repo/semantics/altIdentifier/doi/10.1161/JAHA.112.003855 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
American Heart Association |
publisher.none.fl_str_mv |
American Heart Association |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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13.13397 |