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.