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Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells
Peroxiredoxin 3 (PRX3), a typical 2-Cys peroxiredoxin located exclusively in the mitochondrial matrix, is the principal peroxidase responsible for metabolizing mitochondrial hydrogen peroxide, a byproduct of cellular respiration originating from the mitochondrial electron transport chain. Mitochondr...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297934/ https://www.ncbi.nlm.nih.gov/pubmed/25462069 http://dx.doi.org/10.1016/j.redox.2014.11.003 |
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author | Cunniff, Brian Wozniak, Alexandra N. Sweeney, Patrick DeCosta, Kendra Heintz, Nicholas H. |
author_facet | Cunniff, Brian Wozniak, Alexandra N. Sweeney, Patrick DeCosta, Kendra Heintz, Nicholas H. |
author_sort | Cunniff, Brian |
collection | PubMed |
description | Peroxiredoxin 3 (PRX3), a typical 2-Cys peroxiredoxin located exclusively in the mitochondrial matrix, is the principal peroxidase responsible for metabolizing mitochondrial hydrogen peroxide, a byproduct of cellular respiration originating from the mitochondrial electron transport chain. Mitochondrial oxidants are produced in excess in cancer cells due to oncogenic transformation and metabolic reorganization, and signals through FOXM1 and other redox-responsive factors to support a hyper-proliferative state. Over-expression of PRX3 in cancer cells has been shown to counteract oncogene-induced senescence and support tumor cell growth and survival making PRX3 a credible therapeutic target. Using malignant mesothelioma (MM) cells stably expressing shRNAs to PRX3 we show that decreased expression of PRX3 alters mitochondrial structure, function and cell cycle kinetics. As compared to control cells, knockdown of PRX3 expression increased mitochondrial membrane potential, basal ATP production, oxygen consumption and extracellular acidification rates. shPRX3 MM cells failed to progress through the cell cycle compared to wild type controls, with increased numbers of cells in G2/M phase. Diminished PRX3 expression also induced mitochondrial hyperfusion similar to the DRP1 inhibitor mdivi-1. Cell cycle progression and changes in mitochondrial networking were rescued by transient expression of either catalase or mitochondrial-targeted catalase, indicating high levels of hydrogen peroxide contribute to perturbations in mitochondrial structure and function in shPRX3 MM cells. Our results indicate that PRX3 levels establish a redox set point that permits MM cells to thrive in response to increased levels of mROS, and that perturbing the redox status governed by PRX3 impairs proliferation by altering cell cycle-dependent dynamics between mitochondrial networking and energy metabolism. |
format | Online Article Text |
id | pubmed-4297934 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-42979342015-01-21 Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells Cunniff, Brian Wozniak, Alexandra N. Sweeney, Patrick DeCosta, Kendra Heintz, Nicholas H. Redox Biol Article Peroxiredoxin 3 (PRX3), a typical 2-Cys peroxiredoxin located exclusively in the mitochondrial matrix, is the principal peroxidase responsible for metabolizing mitochondrial hydrogen peroxide, a byproduct of cellular respiration originating from the mitochondrial electron transport chain. Mitochondrial oxidants are produced in excess in cancer cells due to oncogenic transformation and metabolic reorganization, and signals through FOXM1 and other redox-responsive factors to support a hyper-proliferative state. Over-expression of PRX3 in cancer cells has been shown to counteract oncogene-induced senescence and support tumor cell growth and survival making PRX3 a credible therapeutic target. Using malignant mesothelioma (MM) cells stably expressing shRNAs to PRX3 we show that decreased expression of PRX3 alters mitochondrial structure, function and cell cycle kinetics. As compared to control cells, knockdown of PRX3 expression increased mitochondrial membrane potential, basal ATP production, oxygen consumption and extracellular acidification rates. shPRX3 MM cells failed to progress through the cell cycle compared to wild type controls, with increased numbers of cells in G2/M phase. Diminished PRX3 expression also induced mitochondrial hyperfusion similar to the DRP1 inhibitor mdivi-1. Cell cycle progression and changes in mitochondrial networking were rescued by transient expression of either catalase or mitochondrial-targeted catalase, indicating high levels of hydrogen peroxide contribute to perturbations in mitochondrial structure and function in shPRX3 MM cells. Our results indicate that PRX3 levels establish a redox set point that permits MM cells to thrive in response to increased levels of mROS, and that perturbing the redox status governed by PRX3 impairs proliferation by altering cell cycle-dependent dynamics between mitochondrial networking and energy metabolism. Elsevier 2014-11-18 /pmc/articles/PMC4297934/ /pubmed/25462069 http://dx.doi.org/10.1016/j.redox.2014.11.003 Text en © 2014 The Authors http://creativecommons.org/licenses/by/3.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Cunniff, Brian Wozniak, Alexandra N. Sweeney, Patrick DeCosta, Kendra Heintz, Nicholas H. Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells |
title | Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells |
title_full | Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells |
title_fullStr | Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells |
title_full_unstemmed | Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells |
title_short | Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells |
title_sort | peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297934/ https://www.ncbi.nlm.nih.gov/pubmed/25462069 http://dx.doi.org/10.1016/j.redox.2014.11.003 |
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