Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein

Michel Bernier; Rajib K Paul; Alejandro Martin-Montalvo; Morten Scheibye-Knudsen; Shaoming Song; Hua-Jun He; Sean M Armour; Basil P Hubbard; Vilhelm A Bohr; Lili Wang; Yaping Zong; David A Sinclair; Rafael de Cabo

doi:10.1074/jbc.M110.200311

Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein

Michel Bernier, Rajib K Paul, Alejandro Martin-Montalvo, Morten Scheibye-Knudsen, Shaoming Song, Hua-Jun He, Sean M Armour, Basil P Hubbard, Vilhelm A Bohr, Lili Wang, Yaping Zong, David A Sinclair, Rafael de Cabo

81 Citations (Scopus)

Abstract

In mammals, the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) is regulated by the deacetylase SIRT1. However, whether the newly described non-genomic actions of STAT3 toward mitochondrial oxidative phosphorylation are dependent on SIRT1 is unclear. In this study, Sirt1 gene knock-out murine embryonic fibroblast (MEF) cells were used to delineate the role of SIRT1 in the regulation of STAT3 mitochondrial function. Here, we show that STAT3 mRNA and protein levels and the accumulation of serine-phosphorylated STAT3 in mitochondria were increased significantly in Sirt1-KO cells as compared with wild-type MEFs. Various mitochondrial bioenergetic parameters, such as the oxygen consumption rate in cell cultures, enzyme activities of the electron transport chain complexes in isolated mitochondria, and production of ATP and lactate, indicated that Sirt1-KO cells exhibited higher mitochondrial respiration as compared with wild-type MEFs. Two independent approaches, including ectopic expression of SIRT1 and siRNA-mediated knockdown of STAT3, led to reduction in intracellular ATP levels and increased lactate production in Sirt1-KO cells that were approaching those of wild-type controls. Comparison of profiles of phospho-antibody array data indicated that the deletion of SirT1 was accompanied by constitutive activation of the proinflammatory NF-κB pathway, which is key for STAT3 induction and increased cellular respiration in Sirt1-KO cells. Thus, SIRT1 appears to be a functional regulator of NF-κB-dependent STAT3 expression that induces mitochondrial biogenesis. These results have implications for understanding the interplay between STAT3 and SIRT1 in pro-inflammatory conditions.

Original language	English
Journal	The Journal of Biological Chemistry
Volume	286
Issue number	22
Pages (from-to)	19270-9
Number of pages	10
ISSN	1083-351X
DOIs	https://doi.org/10.1074/jbc.M110.200311
Publication status	Published - 3 Jun 2011

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Bernier, M., Paul, R. K., Martin-Montalvo, A., Scheibye-Knudsen, M., Song, S., He, H-J., Armour, S. M., Hubbard, B. P., Bohr, V. A., Wang, L., Zong, Y., Sinclair, D. A., & de Cabo, R. (2011). Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein. The Journal of Biological Chemistry, 286(22), 19270-9. https://doi.org/10.1074/jbc.M110.200311

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title = "Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein",

abstract = "In mammals, the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) is regulated by the deacetylase SIRT1. However, whether the newly described non-genomic actions of STAT3 toward mitochondrial oxidative phosphorylation are dependent on SIRT1 is unclear. In this study, Sirt1 gene knock-out murine embryonic fibroblast (MEF) cells were used to delineate the role of SIRT1 in the regulation of STAT3 mitochondrial function. Here, we show that STAT3 mRNA and protein levels and the accumulation of serine-phosphorylated STAT3 in mitochondria were increased significantly in Sirt1-KO cells as compared with wild-type MEFs. Various mitochondrial bioenergetic parameters, such as the oxygen consumption rate in cell cultures, enzyme activities of the electron transport chain complexes in isolated mitochondria, and production of ATP and lactate, indicated that Sirt1-KO cells exhibited higher mitochondrial respiration as compared with wild-type MEFs. Two independent approaches, including ectopic expression of SIRT1 and siRNA-mediated knockdown of STAT3, led to reduction in intracellular ATP levels and increased lactate production in Sirt1-KO cells that were approaching those of wild-type controls. Comparison of profiles of phospho-antibody array data indicated that the deletion of SirT1 was accompanied by constitutive activation of the proinflammatory NF-κB pathway, which is key for STAT3 induction and increased cellular respiration in Sirt1-KO cells. Thus, SIRT1 appears to be a functional regulator of NF-κB-dependent STAT3 expression that induces mitochondrial biogenesis. These results have implications for understanding the interplay between STAT3 and SIRT1 in pro-inflammatory conditions.",

author = "Michel Bernier and Paul, {Rajib K} and Alejandro Martin-Montalvo and Morten Scheibye-Knudsen and Shaoming Song and Hua-Jun He and Armour, {Sean M} and Hubbard, {Basil P} and Bohr, {Vilhelm A} and Lili Wang and Yaping Zong and Sinclair, {David A} and {de Cabo}, Rafael",

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AU - Bernier, Michel

AU - Paul, Rajib K

AU - Martin-Montalvo, Alejandro

AU - Scheibye-Knudsen, Morten

AU - Song, Shaoming

AU - He, Hua-Jun

AU - Armour, Sean M

AU - Hubbard, Basil P

AU - Bohr, Vilhelm A

AU - Wang, Lili

AU - Zong, Yaping

AU - Sinclair, David A

AU - de Cabo, Rafael

PY - 2011/6/3

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N2 - In mammals, the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) is regulated by the deacetylase SIRT1. However, whether the newly described non-genomic actions of STAT3 toward mitochondrial oxidative phosphorylation are dependent on SIRT1 is unclear. In this study, Sirt1 gene knock-out murine embryonic fibroblast (MEF) cells were used to delineate the role of SIRT1 in the regulation of STAT3 mitochondrial function. Here, we show that STAT3 mRNA and protein levels and the accumulation of serine-phosphorylated STAT3 in mitochondria were increased significantly in Sirt1-KO cells as compared with wild-type MEFs. Various mitochondrial bioenergetic parameters, such as the oxygen consumption rate in cell cultures, enzyme activities of the electron transport chain complexes in isolated mitochondria, and production of ATP and lactate, indicated that Sirt1-KO cells exhibited higher mitochondrial respiration as compared with wild-type MEFs. Two independent approaches, including ectopic expression of SIRT1 and siRNA-mediated knockdown of STAT3, led to reduction in intracellular ATP levels and increased lactate production in Sirt1-KO cells that were approaching those of wild-type controls. Comparison of profiles of phospho-antibody array data indicated that the deletion of SirT1 was accompanied by constitutive activation of the proinflammatory NF-κB pathway, which is key for STAT3 induction and increased cellular respiration in Sirt1-KO cells. Thus, SIRT1 appears to be a functional regulator of NF-κB-dependent STAT3 expression that induces mitochondrial biogenesis. These results have implications for understanding the interplay between STAT3 and SIRT1 in pro-inflammatory conditions.

AB - In mammals, the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) is regulated by the deacetylase SIRT1. However, whether the newly described non-genomic actions of STAT3 toward mitochondrial oxidative phosphorylation are dependent on SIRT1 is unclear. In this study, Sirt1 gene knock-out murine embryonic fibroblast (MEF) cells were used to delineate the role of SIRT1 in the regulation of STAT3 mitochondrial function. Here, we show that STAT3 mRNA and protein levels and the accumulation of serine-phosphorylated STAT3 in mitochondria were increased significantly in Sirt1-KO cells as compared with wild-type MEFs. Various mitochondrial bioenergetic parameters, such as the oxygen consumption rate in cell cultures, enzyme activities of the electron transport chain complexes in isolated mitochondria, and production of ATP and lactate, indicated that Sirt1-KO cells exhibited higher mitochondrial respiration as compared with wild-type MEFs. Two independent approaches, including ectopic expression of SIRT1 and siRNA-mediated knockdown of STAT3, led to reduction in intracellular ATP levels and increased lactate production in Sirt1-KO cells that were approaching those of wild-type controls. Comparison of profiles of phospho-antibody array data indicated that the deletion of SirT1 was accompanied by constitutive activation of the proinflammatory NF-κB pathway, which is key for STAT3 induction and increased cellular respiration in Sirt1-KO cells. Thus, SIRT1 appears to be a functional regulator of NF-κB-dependent STAT3 expression that induces mitochondrial biogenesis. These results have implications for understanding the interplay between STAT3 and SIRT1 in pro-inflammatory conditions.

U2 - 10.1074/jbc.M110.200311

DO - 10.1074/jbc.M110.200311

M3 - Journal article

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SN - 0021-9258

VL - 286

SP - 19270

EP - 19279

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 22

ER -

Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein

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