Stat3 binds to mitochondrial DNA and regulates mitochondrial gene expression in keratinocytes

The nuclear transcription factor Stat3 has recently been reported to have a localized mitochondrial regulatory function. Current data suggest that mitochondrial Stat3 (mitoStat3) is necessary for maximal mitochondrial activity and for Ras-mediated transformation independent of Stat3 nuclear activity. We have previously shown that Stat3 plays a pivotal role in epithelial carcinogenesis. Therefore, the aim of the current study was to determine the role of mitoStat3 in epidermal keratinocytes. Herein, we show that normal and neoplastic keratinocytes contain a pool of mitoStat3. EGF and TPA induce Stat3 mitochondrial translocation mediated through phosphorylation of Stat3 at Ser(727). In addition, we report that mitoStat3 binds mitochondrial DNA (mtDNA) and associates with the mitochondrial transcription factor TFAM. Furthermore, Stat3 ablation resulted in an increase of mitochondrial encoded gene transcripts. An increase in key nuclear-encoded metabolic genes, PGC-1α and NRF-1, was also observed in Stat3 null keratinocytes, however no changes in nuclear-encoded ETC gene transcripts or mtDNA copy number were observed. Collectively, our findings suggest a heretofore-unreported function for mitoStat3 as a potential mitochondrial transcription factor in keratinocytes. This mitoStat3-mtDNA interaction may represent an alternate signaling pathway that could alter mitochondrial function and biogenesis and play a role in tumorigenesis.