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Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduces mitochondrial ROS production

Meier, Jeremy A.; Hyun, Moonjung; Cantwell, Marc; Raza, Ali; Mertens, Claudia; Raje, Vidisha; Sisler, Jennifer; Tracy, Erin; Torres-Odio, Sylvia; Gispert, Suzana; Shaw, Peter E.; Baumann, Heinz; Bandyopadhyay, Dipankar; Takabe, Kazuaki; Larner, Andrew C.

Authors

Jeremy A. Meier

Moonjung Hyun

Marc Cantwell

Ali Raza

Claudia Mertens

Vidisha Raje

Jennifer Sisler

Erin Tracy

Sylvia Torres-Odio

Suzana Gispert

Peter E. Shaw

Heinz Baumann

Dipankar Bandyopadhyay

Kazuaki Takabe

Andrew C. Larner



Abstract

Signal Transducer and Activator of Transcription 3 (STAT3) has been tied to various physiological and pathological functions, mainly as a transcription factor that translocates to the nucleus upon tyrosine phosphorylation induced by cytokine stimulation. In addition, a small pool of STAT3 resides in the mitochondria where it serves as a sensor for various metabolic stressors including reactive oxygen species (ROS). Mitochondrially-localized STAT3 largely exerts its effects through direct or indirect regulation of the activity of the electron transport chain (ETC). It has been assumed that STAT3 amounts in the mitochondria are static. We showed that various stimuli, including oxidative stress and cytokines, triggered a signaling cascade that resulted in a rapid loss of mitochondrially-localized STAT3. Recovery of the mitochondrial pool of STAT3 over time depended upon phosphorylation of Ser727 in STAT3 and new protein synthesis. Under these conditions, mitochondrially-localized STAT3 also became competent to bind to cyclophilin D (CypD). Binding of STAT3 to CypD was mediated by the N-terminus of STAT3, which was also important for reducing mitochondrial ROS production after oxidative stress. These results outline a role for mitochondrially-localized STAT3 in sensing and responding to external stimuli.

Journal Article Type Article
Publication Date Mar 28, 2017
Journal Science Signaling
Print ISSN 1945-0877
Electronic ISSN 1937-9145
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 10
Issue 472
Article Number eaag2588
APA6 Citation Meier, J. A., Hyun, M., Cantwell, M., Raza, A., Mertens, C., Raje, V., …Larner, A. C. (2017). Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduces mitochondrial ROS production. Science Signaling, 10(472), https://doi.org/10.1126/scisignal.aag2588
DOI https://doi.org/10.1126/scisignal.aag2588
Publisher URL http://stke.sciencemag.org/content/10/472/eaag2588.long
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information This manuscript has been accepted for publication in Science Signaling. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencesignaling.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS.

This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in
Science Signaling, Vol. 10, issue 472 on 28/03/2017, DOI: 10.1126/scisignal.aag2588.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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