Mitochondrial STAT3 regulates proliferation of tissue stem cells.

The STAT3 transcription factor, acting both in the nucleus and mitochondria, is needed to maintain embryonic stem cell pluripotency and promote proliferation. In this work, using zebrafish, we determined in vivo that mitochondrial STAT3 regulates mtDNA transcription in embryonic and larval stem cell niches and that this activity is fundamental in determining proliferation rates. To dissect the molecular requirements for mitoSTAT3 functions, we used drugs and missense mutations to kinase-targeted STAT3 residues. As a result, we demonstrated that STAT3 import inside mitochondria requires Y705 phosphorylation by Jak2, while its mitochondrial transcriptional activity, as well as its replication potential, depends on the MAPK target S727. Moreover, while STAT3-dependent mtDNA transcription is needed and sufficient to induce cell proliferation, it is not required to maintain stem-like phenotype in the tectal niche. Surprisingly, STAT3-dependent increase of mitochondrial transcription seems independent from STAT3 binding to DNA and does not originate from STAT3 regulation of mtDNA replication.