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.

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.

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), Article eaag2588. https://doi.org/10.1126/scisignal.aag2588

• Journal Article Type: Article
• Acceptance Date: Mar 8, 2017
• Online Publication Date: Mar 28, 2017
• Publication Date: Mar 28, 2017
• Deposit Date: Apr 6, 2017
• Publicly Available Date: Apr 6, 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
• DOI: https://doi.org/10.1126/scisignal.aag2588
• Public URL: https://nottingham-repository.worktribe.com/output/852731
• Publisher URL: http://stke.sciencemag.org/content/10/472/eaag2588.long
• 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.