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Disruption of Astrocyte STAT3 Signaling Decreases Mitochondrial Function and Increases Oxidative Stress In Vitro

BACKGROUND: Astrocytes exert a wide variety of functions in health and disease and respond to a wide range of signaling pathways, including members of the Janus-kinase signal transducers and activators of transcription (Jak-STAT) family. We have recently shown that STAT3 is an important regulator of...

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Autores principales: Sarafian, Theodore A., Montes, Cindy, Imura, Tetsuya, Qi, Jingwei, Coppola, Giovanni, Geschwind, Daniel H., Sofroniew, Michael V.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835741/
https://www.ncbi.nlm.nih.gov/pubmed/20224768
http://dx.doi.org/10.1371/journal.pone.0009532
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author Sarafian, Theodore A.
Montes, Cindy
Imura, Tetsuya
Qi, Jingwei
Coppola, Giovanni
Geschwind, Daniel H.
Sofroniew, Michael V.
author_facet Sarafian, Theodore A.
Montes, Cindy
Imura, Tetsuya
Qi, Jingwei
Coppola, Giovanni
Geschwind, Daniel H.
Sofroniew, Michael V.
author_sort Sarafian, Theodore A.
collection PubMed
description BACKGROUND: Astrocytes exert a wide variety of functions in health and disease and respond to a wide range of signaling pathways, including members of the Janus-kinase signal transducers and activators of transcription (Jak-STAT) family. We have recently shown that STAT3 is an important regulator of astrocyte reactivity after spinal cord injury in vivo [1]. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used both a conditional gene deletion strategy that targets the deletion of STAT3 selectively to astrocytes (STAT3-CKO), and a pharmacological inhibitor of JAK-2, AG490, in cultured astrocytes in vitro, to investigate potential functions and molecules influenced by STAT3 signaling in relation to mitochondrial function and oxidative stress. Our findings show that the absence of STAT3 signaling in astrocytes leads to (i) increased production of superoxide anion and other reactive oxygen species and decreased level of glutathione, (ii) decreased mitochondrial membrane potential and decreased ATP production, and (iii) decreased rate of cell proliferation. Many of the differences observed in STAT3-CKO astrocytes were distinctly altered by exposure to rotenone, suggesting a role for complex I of the mitochondrial electron transport chain. Gene expression microarray studies identified numerous changes in STAT3-CKO cells that may have contributed to the identified deficits in cell function. CONCLUSIONS/SIGNIFICANCE: Taken together, these STAT3-dependent alterations in cell function and gene expression have relevance to both reactive gliosis and to the support and protection of surrounding cells in neural tissue.
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spelling pubmed-28357412010-03-12 Disruption of Astrocyte STAT3 Signaling Decreases Mitochondrial Function and Increases Oxidative Stress In Vitro Sarafian, Theodore A. Montes, Cindy Imura, Tetsuya Qi, Jingwei Coppola, Giovanni Geschwind, Daniel H. Sofroniew, Michael V. PLoS One Research Article BACKGROUND: Astrocytes exert a wide variety of functions in health and disease and respond to a wide range of signaling pathways, including members of the Janus-kinase signal transducers and activators of transcription (Jak-STAT) family. We have recently shown that STAT3 is an important regulator of astrocyte reactivity after spinal cord injury in vivo [1]. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used both a conditional gene deletion strategy that targets the deletion of STAT3 selectively to astrocytes (STAT3-CKO), and a pharmacological inhibitor of JAK-2, AG490, in cultured astrocytes in vitro, to investigate potential functions and molecules influenced by STAT3 signaling in relation to mitochondrial function and oxidative stress. Our findings show that the absence of STAT3 signaling in astrocytes leads to (i) increased production of superoxide anion and other reactive oxygen species and decreased level of glutathione, (ii) decreased mitochondrial membrane potential and decreased ATP production, and (iii) decreased rate of cell proliferation. Many of the differences observed in STAT3-CKO astrocytes were distinctly altered by exposure to rotenone, suggesting a role for complex I of the mitochondrial electron transport chain. Gene expression microarray studies identified numerous changes in STAT3-CKO cells that may have contributed to the identified deficits in cell function. CONCLUSIONS/SIGNIFICANCE: Taken together, these STAT3-dependent alterations in cell function and gene expression have relevance to both reactive gliosis and to the support and protection of surrounding cells in neural tissue. Public Library of Science 2010-03-10 /pmc/articles/PMC2835741/ /pubmed/20224768 http://dx.doi.org/10.1371/journal.pone.0009532 Text en Sarafian et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sarafian, Theodore A.
Montes, Cindy
Imura, Tetsuya
Qi, Jingwei
Coppola, Giovanni
Geschwind, Daniel H.
Sofroniew, Michael V.
Disruption of Astrocyte STAT3 Signaling Decreases Mitochondrial Function and Increases Oxidative Stress In Vitro
title Disruption of Astrocyte STAT3 Signaling Decreases Mitochondrial Function and Increases Oxidative Stress In Vitro
title_full Disruption of Astrocyte STAT3 Signaling Decreases Mitochondrial Function and Increases Oxidative Stress In Vitro
title_fullStr Disruption of Astrocyte STAT3 Signaling Decreases Mitochondrial Function and Increases Oxidative Stress In Vitro
title_full_unstemmed Disruption of Astrocyte STAT3 Signaling Decreases Mitochondrial Function and Increases Oxidative Stress In Vitro
title_short Disruption of Astrocyte STAT3 Signaling Decreases Mitochondrial Function and Increases Oxidative Stress In Vitro
title_sort disruption of astrocyte stat3 signaling decreases mitochondrial function and increases oxidative stress in vitro
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835741/
https://www.ncbi.nlm.nih.gov/pubmed/20224768
http://dx.doi.org/10.1371/journal.pone.0009532
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