Signal Transducer and Activator of Transcription (STAT)3 is a key signalling molecule that is activated by cytokines and growth factors to regulate immune responses, metabolism, proliferation and cell death. Whilst the activity of STAT3 is crucial for sustenance of life, its dysregulated function results in a vast number of human cancers. STAT3 has recently been found to modulate mitochondrial activity via the electron transport chain (ETC) in both healthy and cancerous tissues. STAT3 has been shown to interact specifically and directly with complex I, however the mitochondrial pool of STAT3 is vastly outnumbered by complex I. This suggests that a direct interaction is unlikely to be responsible for the alterations in mitochondrial metabolic activity.
In order to investigate the mitochondrial role of STAT3, we isolated STAT3 from mitochondrial fractions of Ras-driven lung cancer cell line (A549) and identified its interactors using mass spectrometry. Most of these interacting proteins were either RNA handling proteins or proteins of the mitochondrial ribosome complex. We have shown that STAT3 forms a stable 400 kDa complex with the heterodimer protein couple LRPPRC/SLIRP, which is a known regulator of mitochondrial post-transcriptional gene expression. STAT3 loss resulted in drastically reduced steady state levels of polyadenylated mitochondrial RNA. On further examination, we found that the absence of STAT3 led to instability of the mitochondrial polyadenylated RNA. We have confirmed that this is not due to changes in mitochondrial DNA copy number, differences in mitochondrial transcription kinetics or mitochondrial RNA processing. Furthermore, RNA instability accompanied with a delay in mitochondrial translational kinetics. We set forth that the ability of STAT3 to regulate mitochondrial transcription and translation is the fundamental mechanism by which a small pool of STAT3 can regulate highly abundant key component proteins of the ETC. Together these findings for the first time demonstrate a mechanistic role of STAT3 in the mitochondria.