Research ArticleCell Biology

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

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Science Signaling  28 Mar 2017:
Vol. 10, Issue 472, eaag2588
DOI: 10.1126/scisignal.aag2588

Dynamic regulation of mitochondrial STAT3

In cytokine-stimulated cells, the transcription factor STAT3 translocates from the cytoplasm to the nucleus to transcriptionally activate genes involved in stress responses. STAT3 also functions in the mitochondria to regulate cellular respiration. Meier et al. found that oxidative stress and cytokines depleted the mitochondrial pool of STAT3, and restoration of this pool required the chaperone protein cyclophilin D. Moreover, the restored STAT3 suppressed the stress-induced generation of reactive oxygen species in the mitochondria. These results suggest that the mitochondrial pool is dynamically regulated similar to the cytoplasmic and nuclear pools of STAT3 and that the mitochondrial pool is responsive to external stimuli.


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.

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