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Sci Signal. 2017 Mar 28;10(472). pii: eaag2588. doi: 10.1126/scisignal.aag2588.

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

Author information

1
Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA.
2
Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
3
Division of Surgical Oncology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
4
Laboratory of Molecular Cell Biology, Rockefeller University, New York, NY 10065, USA.
5
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
6
Experimental Neurology, Goethe University Medical School, Frankfurt am Main, Germany.
7
School of Life Sciences, University of Nottingham, Nottingham, U.K.
8
Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
9
Division of Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
10
Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA.
11
Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA. andrew.larner@vcuhealth.org.

Abstract

Signal transducer and activator of transcription 3 (STAT3) is associated with 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 the amounts of STAT3 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 on 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 amino 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.

PMID:
28351946
PMCID:
PMC5502128
DOI:
10.1126/scisignal.aag2588
[Indexed for MEDLINE]
Free PMC Article

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