Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study
- Autores
- Aon, Miguel Antonio; Stanley, Brian Alan; Sivakumaran, Vidhya; Kembro, Jackelyn Melissa; O'Rourke, Brian; Paolocci, Nazareno; Cortassa, Sonia
- Año de publicación
- 2012
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- The net emission of hydrogen peroxide (H2O2) from mitochondria results from the balance between reactive oxygen species (ROS) continuously generated in the respiratory chain and ROS scavenging. The relative contribution of the two major antioxidant systems in the mitochondrial matrix, glutathione (GSH) and thioredoxin (Trx), has not been assessed. In this paper, we examine this key question via combined experimental and theoretical approaches, using isolated heart mitochondria from mouse, rat, and guinea pig. As compared with untreated control mitochondria, selective inhibition of Trx reductase with auranofin along with depletion of GSH with 2,4-dinitrochlorobenzene led to a species-dependent increase in H2O2 emission flux of 17, 11, and 6 fold in state 4 and 15, 7, and 8 fold in state 3 for mouse, rat, and guinea pig mitochondria, respectively. The maximal H2O2 emission as a percentage of the total O2 consumption flux was 11%/2.3% for mouse in states 4 and 3 followed by 2%/0.25% and 0.74%/0.29% in the rat and guinea pig, respectively. A minimal computational model accounting for the kinetics of GSH/Trx systems was developed and was able to simulate increase in H2O2 emission fluxes when both scavenging systems were inhibited separately or together. Model simulations suggest that GSH/Trx systems act in concert. When the scavenging capacity of either one of them saturates during H2O2 overload, they relieve each other until complete saturation, when maximal ROS emission occurs. Quantitatively, these results converge on the idea that GSH/Trx scavenging systems in mitochondria are both essential for keeping minimal levels of H2O2 emission, especially during state 3 respiration, when the energetic output is maximal. This suggests that the very low levels of H2O2 emission observed during forward electron transport in the respiratory chain are a result of the well-orchestrated actions of the two antioxidant systems working continuously to offset ROS production.
Fil: Aon, Miguel Antonio. University Johns Hopkins; Estados Unidos
Fil: Stanley, Brian Alan. University Johns Hopkins; Estados Unidos
Fil: Sivakumaran, Vidhya. University Johns Hopkins; Estados Unidos
Fil: Kembro, Jackelyn Melissa. University Johns Hopkins; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina
Fil: O'Rourke, Brian. University Johns Hopkins; Estados Unidos
Fil: Paolocci, Nazareno. University Johns Hopkins; Estados Unidos
Fil: Cortassa, Sonia. University Johns Hopkins; Estados Unidos - Materia
-
GLUTATHIONE SYSTEM
THIOREDOXIN SYSTEM
ROS - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/42623
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Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational studyAon, Miguel AntonioStanley, Brian AlanSivakumaran, VidhyaKembro, Jackelyn MelissaO'Rourke, BrianPaolocci, NazarenoCortassa, SoniaGLUTATHIONE SYSTEMTHIOREDOXIN SYSTEMROShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The net emission of hydrogen peroxide (H2O2) from mitochondria results from the balance between reactive oxygen species (ROS) continuously generated in the respiratory chain and ROS scavenging. The relative contribution of the two major antioxidant systems in the mitochondrial matrix, glutathione (GSH) and thioredoxin (Trx), has not been assessed. In this paper, we examine this key question via combined experimental and theoretical approaches, using isolated heart mitochondria from mouse, rat, and guinea pig. As compared with untreated control mitochondria, selective inhibition of Trx reductase with auranofin along with depletion of GSH with 2,4-dinitrochlorobenzene led to a species-dependent increase in H2O2 emission flux of 17, 11, and 6 fold in state 4 and 15, 7, and 8 fold in state 3 for mouse, rat, and guinea pig mitochondria, respectively. The maximal H2O2 emission as a percentage of the total O2 consumption flux was 11%/2.3% for mouse in states 4 and 3 followed by 2%/0.25% and 0.74%/0.29% in the rat and guinea pig, respectively. A minimal computational model accounting for the kinetics of GSH/Trx systems was developed and was able to simulate increase in H2O2 emission fluxes when both scavenging systems were inhibited separately or together. Model simulations suggest that GSH/Trx systems act in concert. When the scavenging capacity of either one of them saturates during H2O2 overload, they relieve each other until complete saturation, when maximal ROS emission occurs. Quantitatively, these results converge on the idea that GSH/Trx scavenging systems in mitochondria are both essential for keeping minimal levels of H2O2 emission, especially during state 3 respiration, when the energetic output is maximal. This suggests that the very low levels of H2O2 emission observed during forward electron transport in the respiratory chain are a result of the well-orchestrated actions of the two antioxidant systems working continuously to offset ROS production.Fil: Aon, Miguel Antonio. University Johns Hopkins; Estados UnidosFil: Stanley, Brian Alan. University Johns Hopkins; Estados UnidosFil: Sivakumaran, Vidhya. University Johns Hopkins; Estados UnidosFil: Kembro, Jackelyn Melissa. University Johns Hopkins; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: O'Rourke, Brian. University Johns Hopkins; Estados UnidosFil: Paolocci, Nazareno. University Johns Hopkins; Estados UnidosFil: Cortassa, Sonia. University Johns Hopkins; Estados UnidosRockefeller University Press2012-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/42623Aon, Miguel Antonio; Stanley, Brian Alan; Sivakumaran, Vidhya; Kembro, Jackelyn Melissa; O'Rourke, Brian; et al.; Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study; Rockefeller University Press; Journal Of General Physiology; 139; 6; 6-2012; 479-4910022-12951540-7748CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://jgp.rupress.org/content/139/6/479info:eu-repo/semantics/altIdentifier/doi/10.1085/jgp.201210772info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:41:04Zoai:ri.conicet.gov.ar:11336/42623instacron: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:34982025-09-29 09:41:04.373CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study |
title |
Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study |
spellingShingle |
Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study Aon, Miguel Antonio GLUTATHIONE SYSTEM THIOREDOXIN SYSTEM ROS |
title_short |
Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study |
title_full |
Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study |
title_fullStr |
Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study |
title_full_unstemmed |
Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study |
title_sort |
Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study |
dc.creator.none.fl_str_mv |
Aon, Miguel Antonio Stanley, Brian Alan Sivakumaran, Vidhya Kembro, Jackelyn Melissa O'Rourke, Brian Paolocci, Nazareno Cortassa, Sonia |
author |
Aon, Miguel Antonio |
author_facet |
Aon, Miguel Antonio Stanley, Brian Alan Sivakumaran, Vidhya Kembro, Jackelyn Melissa O'Rourke, Brian Paolocci, Nazareno Cortassa, Sonia |
author_role |
author |
author2 |
Stanley, Brian Alan Sivakumaran, Vidhya Kembro, Jackelyn Melissa O'Rourke, Brian Paolocci, Nazareno Cortassa, Sonia |
author2_role |
author author author author author author |
dc.subject.none.fl_str_mv |
GLUTATHIONE SYSTEM THIOREDOXIN SYSTEM ROS |
topic |
GLUTATHIONE SYSTEM THIOREDOXIN SYSTEM ROS |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
The net emission of hydrogen peroxide (H2O2) from mitochondria results from the balance between reactive oxygen species (ROS) continuously generated in the respiratory chain and ROS scavenging. The relative contribution of the two major antioxidant systems in the mitochondrial matrix, glutathione (GSH) and thioredoxin (Trx), has not been assessed. In this paper, we examine this key question via combined experimental and theoretical approaches, using isolated heart mitochondria from mouse, rat, and guinea pig. As compared with untreated control mitochondria, selective inhibition of Trx reductase with auranofin along with depletion of GSH with 2,4-dinitrochlorobenzene led to a species-dependent increase in H2O2 emission flux of 17, 11, and 6 fold in state 4 and 15, 7, and 8 fold in state 3 for mouse, rat, and guinea pig mitochondria, respectively. The maximal H2O2 emission as a percentage of the total O2 consumption flux was 11%/2.3% for mouse in states 4 and 3 followed by 2%/0.25% and 0.74%/0.29% in the rat and guinea pig, respectively. A minimal computational model accounting for the kinetics of GSH/Trx systems was developed and was able to simulate increase in H2O2 emission fluxes when both scavenging systems were inhibited separately or together. Model simulations suggest that GSH/Trx systems act in concert. When the scavenging capacity of either one of them saturates during H2O2 overload, they relieve each other until complete saturation, when maximal ROS emission occurs. Quantitatively, these results converge on the idea that GSH/Trx scavenging systems in mitochondria are both essential for keeping minimal levels of H2O2 emission, especially during state 3 respiration, when the energetic output is maximal. This suggests that the very low levels of H2O2 emission observed during forward electron transport in the respiratory chain are a result of the well-orchestrated actions of the two antioxidant systems working continuously to offset ROS production. Fil: Aon, Miguel Antonio. University Johns Hopkins; Estados Unidos Fil: Stanley, Brian Alan. University Johns Hopkins; Estados Unidos Fil: Sivakumaran, Vidhya. University Johns Hopkins; Estados Unidos Fil: Kembro, Jackelyn Melissa. University Johns Hopkins; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina Fil: O'Rourke, Brian. University Johns Hopkins; Estados Unidos Fil: Paolocci, Nazareno. University Johns Hopkins; Estados Unidos Fil: Cortassa, Sonia. University Johns Hopkins; Estados Unidos |
description |
The net emission of hydrogen peroxide (H2O2) from mitochondria results from the balance between reactive oxygen species (ROS) continuously generated in the respiratory chain and ROS scavenging. The relative contribution of the two major antioxidant systems in the mitochondrial matrix, glutathione (GSH) and thioredoxin (Trx), has not been assessed. In this paper, we examine this key question via combined experimental and theoretical approaches, using isolated heart mitochondria from mouse, rat, and guinea pig. As compared with untreated control mitochondria, selective inhibition of Trx reductase with auranofin along with depletion of GSH with 2,4-dinitrochlorobenzene led to a species-dependent increase in H2O2 emission flux of 17, 11, and 6 fold in state 4 and 15, 7, and 8 fold in state 3 for mouse, rat, and guinea pig mitochondria, respectively. The maximal H2O2 emission as a percentage of the total O2 consumption flux was 11%/2.3% for mouse in states 4 and 3 followed by 2%/0.25% and 0.74%/0.29% in the rat and guinea pig, respectively. A minimal computational model accounting for the kinetics of GSH/Trx systems was developed and was able to simulate increase in H2O2 emission fluxes when both scavenging systems were inhibited separately or together. Model simulations suggest that GSH/Trx systems act in concert. When the scavenging capacity of either one of them saturates during H2O2 overload, they relieve each other until complete saturation, when maximal ROS emission occurs. Quantitatively, these results converge on the idea that GSH/Trx scavenging systems in mitochondria are both essential for keeping minimal levels of H2O2 emission, especially during state 3 respiration, when the energetic output is maximal. This suggests that the very low levels of H2O2 emission observed during forward electron transport in the respiratory chain are a result of the well-orchestrated actions of the two antioxidant systems working continuously to offset ROS production. |
publishDate |
2012 |
dc.date.none.fl_str_mv |
2012-06 |
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/11336/42623 Aon, Miguel Antonio; Stanley, Brian Alan; Sivakumaran, Vidhya; Kembro, Jackelyn Melissa; O'Rourke, Brian; et al.; Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study; Rockefeller University Press; Journal Of General Physiology; 139; 6; 6-2012; 479-491 0022-1295 1540-7748 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/42623 |
identifier_str_mv |
Aon, Miguel Antonio; Stanley, Brian Alan; Sivakumaran, Vidhya; Kembro, Jackelyn Melissa; O'Rourke, Brian; et al.; Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study; Rockefeller University Press; Journal Of General Physiology; 139; 6; 6-2012; 479-491 0022-1295 1540-7748 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://jgp.rupress.org/content/139/6/479 info:eu-repo/semantics/altIdentifier/doi/10.1085/jgp.201210772 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Rockefeller University Press |
publisher.none.fl_str_mv |
Rockefeller University Press |
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) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
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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1844613298554667008 |
score |
13.070432 |