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

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

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Article numbereaag2588
JournalScience signaling
Volume10
Issue number472
DOIs
StatePublished - Mar 28 2017

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