biostudies-literatureUnknown25(9)Kim HAlthough it is reported that mitochondria-localized nuclear transcription factors (TFs) regulate mitochondrial processes such as apoptosis and mitochondrial transcription/respiration, the functions and mechanisms of mitochondrial dynamics regulated by mitochondria-localized nuclear TFs are yet to be fully characterized. Here, we identify STAT6 as a mitochondrial protein that is localized in the outer membrane of mitochondria (OMM). STAT6 in OMM inhibits mitochondrial fusion by blocking MFN2 dimerization. This implies that STAT6 has a critical role in mitochondrial dynamics. Moreover, mitochondrial accumulation of STAT6 in response to hypoxic conditions reveals that STAT6 is a regulator of mitochondrial processes including fusion/fission mechanisms.iScience104923https://www.ebi.ac.uk/biostudies/studies/S-EPMC9440285biostudies-literatureSTAT6 in mitochondrial outer membrane impairs mitochondrial fusion by inhibiting MFN2 dimerization.PMC9440285Kim HPark SJJou IfalseSTAT6 in mitochondrial outer membrane impairs mitochondrial fusion by inhibiting MFN2 dimerization.Although it is reported that mitochondria-localized nuclear transcription factors (TFs) regulate mitochondrial processes such as apoptosis and mitochondrial transcription/respiration, the functions and mechanisms of mitochondrial dynamics regulated by mitochondria-localized nuclear TFs are yet to be fully characterized. Here, we identify STAT6 as a mitochondrial protein that is localized in the outer membrane of mitochondria (OMM). STAT6 in OMM inhibits mitochondrial fusion by blocking MFN2 dimerization. This implies that STAT6 has a critical role in mitochondrial dynamics. Moreover, mitochondrial accumulation of STAT6 in response to hypoxic conditions reveals that STAT6 is a regulator of mitochondrial processes including fusion/fission mechanisms.2022-01-01T00:00:00Z2022 Sep2025-04-04T13:33:36.475Z2025-02-19T04:02:36.461ZS-EPMC94402853606518910.1016/j.isci.2022.104923