Essential role of mitochondrial Stat3 in p38^MAPK mediated apoptosis under oxidative stress

Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3^Y705 contributes to its nucleic translocation, while phospho-Stat3^S727 leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well-characterized signaling pathways interplaying with Stat3^Y705, little is known about Stat3^S727. In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to H₂O₂ or hypoxia using siRNA and CRISPR/Cas9 genome-editing. We found dysregulation of mitochondrial activity, which was associated with excessive ROS formation and reduced mitochondrial membrane potential, and observed a synergistic effect for oxidative stress-mediated apoptosis in Stat3-KD cells or cells carrying Stat3^Y705F, but not Stat3^S727D, suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38^MAPK was involved and adding antioxidants, p38^MAPK inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38^MAPK-mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy.