Rotenone-induced reactive oxygen species signal the recruitment of STAT3 to mitochondria

STAT3, a transcription factor involved in various physiological and pathological processes, is also present in mitochondria. Mitochondrial STAT3 regulates complex I activity and reactive oxygen species (ROS) production, yet the mechanisms governing its translocation to mitochondria remain poorly understood. In this study, we show that rotenone-induced ROS triggers the Ser727 phosphorylation of STAT3 and its increased mitochondrial localisation. Furthermore, we show that STAT3-depleted cells display increased ROS levels during rotenone treatment. Targeted expression in mitochondria of wild-type STAT3 - but not S727A mutant - lowers ROS levels, indicating the importance of Ser727 phosphorylation, both in rotenone-induced mitochondrial targeting and quenching of ROS levels. Together, our results demonstrate a novel STAT3-mediated feedback mechanism to maintain redox homeostasis during stress.