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Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria

Mitochondria are critical sources of hydrogen peroxide (H(2)O(2)), an important secondary messenger in mammalian cells. Recent work has shown that O(2)(•-)/H(2)O(2) emission from individual sites of production in mitochondria is regulated by protein S-glutathionylation. Here, we conducted the first...

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Detalles Bibliográficos
Autores principales: Chalker, Julia, Gardiner, Danielle, Kuksal, Nidhi, Mailloux, Ryan J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773472/
https://www.ncbi.nlm.nih.gov/pubmed/29274570
http://dx.doi.org/10.1016/j.redox.2017.12.006
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author Chalker, Julia
Gardiner, Danielle
Kuksal, Nidhi
Mailloux, Ryan J.
author_facet Chalker, Julia
Gardiner, Danielle
Kuksal, Nidhi
Mailloux, Ryan J.
author_sort Chalker, Julia
collection PubMed
description Mitochondria are critical sources of hydrogen peroxide (H(2)O(2)), an important secondary messenger in mammalian cells. Recent work has shown that O(2)(•-)/H(2)O(2) emission from individual sites of production in mitochondria is regulated by protein S-glutathionylation. Here, we conducted the first examination of O(2)(•-)/H(2)O(2) release rates from cardiac and liver mitochondria isolated from mice deficient for glutaredoxin-2 (GRX2), a matrix-associated thiol oxidoreductase that facilitates the S-glutathionylation and deglutathionylation of proteins. Liver mitochondria isolated from mice heterozygous (GRX2+/-) and homozygous (GRX2-/-) for glutaredoxin-2 displayed a significant decrease in O(2)(•-)/H(2)O(2) release when oxidizing pyruvate or 2-oxoglutarate. The genetic deletion of the Grx2 gene was associated with increased protein expression of pyruvate dehydrogenase (PDH) but not 2-oxoglutarate dehydrogenase (OGDH). By contrast, O(2)(•-)/H(2)O(2) production was augmented in cardiac mitochondria from GRX2+/- and GRX2-/- mice metabolizing pyruvate or 2-oxoglutarate which was associated with decreased PDH and OGDH protein levels. ROS production was augmented in liver and cardiac mitochondria metabolizing succinate. Inhibitor studies revealed that OGDH and Complex III served as high capacity ROS release sites in liver mitochondria. By contrast, Complex I and Complex III were found to be the chief O(2)(•-)/H(2)O(2) emitters in cardiac mitochondria. These findings identify an essential role for GRX2 in regulating O(2)(•-)/H(2)O(2) release from mitochondria in liver and cardiac tissue. Our results demonstrate that the GRX2-mediated regulation of O(2)(•-)/H(2)O(2) release through the S-glutathionylation of mitochondrial proteins may play an integral role in controlling cellular ROS signaling.
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spelling pubmed-57734722018-01-29 Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria Chalker, Julia Gardiner, Danielle Kuksal, Nidhi Mailloux, Ryan J. Redox Biol Research Paper Mitochondria are critical sources of hydrogen peroxide (H(2)O(2)), an important secondary messenger in mammalian cells. Recent work has shown that O(2)(•-)/H(2)O(2) emission from individual sites of production in mitochondria is regulated by protein S-glutathionylation. Here, we conducted the first examination of O(2)(•-)/H(2)O(2) release rates from cardiac and liver mitochondria isolated from mice deficient for glutaredoxin-2 (GRX2), a matrix-associated thiol oxidoreductase that facilitates the S-glutathionylation and deglutathionylation of proteins. Liver mitochondria isolated from mice heterozygous (GRX2+/-) and homozygous (GRX2-/-) for glutaredoxin-2 displayed a significant decrease in O(2)(•-)/H(2)O(2) release when oxidizing pyruvate or 2-oxoglutarate. The genetic deletion of the Grx2 gene was associated with increased protein expression of pyruvate dehydrogenase (PDH) but not 2-oxoglutarate dehydrogenase (OGDH). By contrast, O(2)(•-)/H(2)O(2) production was augmented in cardiac mitochondria from GRX2+/- and GRX2-/- mice metabolizing pyruvate or 2-oxoglutarate which was associated with decreased PDH and OGDH protein levels. ROS production was augmented in liver and cardiac mitochondria metabolizing succinate. Inhibitor studies revealed that OGDH and Complex III served as high capacity ROS release sites in liver mitochondria. By contrast, Complex I and Complex III were found to be the chief O(2)(•-)/H(2)O(2) emitters in cardiac mitochondria. These findings identify an essential role for GRX2 in regulating O(2)(•-)/H(2)O(2) release from mitochondria in liver and cardiac tissue. Our results demonstrate that the GRX2-mediated regulation of O(2)(•-)/H(2)O(2) release through the S-glutathionylation of mitochondrial proteins may play an integral role in controlling cellular ROS signaling. Elsevier 2017-12-14 /pmc/articles/PMC5773472/ /pubmed/29274570 http://dx.doi.org/10.1016/j.redox.2017.12.006 Text en © 2017 Published by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Chalker, Julia
Gardiner, Danielle
Kuksal, Nidhi
Mailloux, Ryan J.
Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria
title Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria
title_full Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria
title_fullStr Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria
title_full_unstemmed Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria
title_short Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria
title_sort characterization of the impact of glutaredoxin-2 (grx2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773472/
https://www.ncbi.nlm.nih.gov/pubmed/29274570
http://dx.doi.org/10.1016/j.redox.2017.12.006
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