PT  - JOURNAL ARTICLE
AU  - Margherita Peron
AU  - Giacomo Meneghetti
AU  - Alberto Dinarello
AU  - Laura Martorano
AU  - Riccardo M. Betto
AU  - Nicola Facchinello
AU  - Natascia Tiso
AU  - Graziano Martello
AU  - Francesco Argenton
TI  - Mitochondrial STAT3 regulates proliferation of tissue stem cells
AID  - 10.1101/2020.07.17.208264
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.17.208264
4099  - http://biorxiv.org/content/early/2020/07/30/2020.07.17.208264.short
4100  - http://biorxiv.org/content/early/2020/07/30/2020.07.17.208264.full
AB  - The STAT3 transcription factor, acting both in the nucleus and mitochondria, maintains embryonic stem cell pluripotency and promotes their 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 determines their proliferation rates. To dissect the molecular requirements for mitochondrial STAT3 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 effect on proliferation, 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 a 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.Competing Interest StatementThe authors have declared no competing interest.