@article{c120227acef84af397ead2a81f48c18a,
title = "Epithelial-Mesenchymal Transition Directs Stem Cell Polarity via Regulation of Mitofusin",
abstract = "Mitochondria are dynamic organelles that have been linked to stem cell homeostasis. However, the mechanisms involved in mitochondrial regulation of stem cell fate determination remain elusive. Here we discover that epithelial-mesenchymal transition (EMT), a key process in cancer progression, induces mitochondrial fusion through regulation of the miR200c-PGC1α-MFN1 pathway. EMT-activated MFN1 forms a complex with PKCζ and is required for PKCζ-mediated NUMB phosphorylation and dissociation from the cortical membrane to direct asymmetric division of mammary stem cells, where fused mitochondria are tethered by MFN1-PKCζ to the cortical membrane and asymmetrically segregated to the stem cell-like progeny with enhanced glutathione synthesis and reactive oxygen species scavenging capacities, allowing sustaining of a self-renewing stem cell pool. Suppression of MFN1 expression leads to equal distribution of the fragmented mitochondria in both progenies that undergo symmetric luminal cell differentiation. Together, this study elucidates an essential role of mitofusin in stem cell fate determination to mediate EMT-associated stemness. Wu et al. reveal that EMT, a key process in cancer progression, activates mitochondrial fusion protein, MFN1, which interacts with cell polarity protein complex to direct asymmetric cell division, allowing stem cell progeny to inherit fused mitochondria with enhanced reactive oxygen species scavenging capacity to sustain the stem cell pool.",
keywords = "cell plasticity, EMT, mammary stem cell, mitochondrial dynamics, mitofusin, stem cell fate, stem cell polarity",
author = "Wu, {Meng Ju} and Chen, {Yu Syuan} and Kim, {Mi Ran} and Chang, {Chao Ching} and Silpa Gampala and Yingsheng Zhang and Yueyang Wang and Chang, {Chih Yu} and Yang, {Jer Yen} and Chang, {Chun Ju}",
note = "Funding Information: We thank Drs. Chi-Hong Chao and Bao-Hong Lee for technical assistance with experiments. We thank Purdue Metabolite Profiling Facility, Histology Laboratory, and Biological Evaluation Facility for experimental consultation and technical assistance. This study was supported by the National Cancer Institute ( R37CA215087 to C.-J.C.), Department of Defense Breast Cancer Breakthrough Award ( W81XWH-1510644 to C.-J.C.), V Foundation for Cancer Research grant ( V2015-019 and D2018-010 to C.-J.C.), Purdue AgSEED grant, and NIH P30CA023168 to the Purdue University Center for Cancer Research in support of the use of facilities. Funding Information: We thank Drs. Chi-Hong Chao and Bao-Hong Lee for technical assistance with experiments. We thank Purdue Metabolite Profiling Facility, Histology Laboratory, and Biological Evaluation Facility for experimental consultation and technical assistance. This study was supported by the National Cancer Institute (R37CA215087 to C.-J.C.), Department of Defense Breast Cancer Breakthrough Award (W81XWH-1510644 to C.-J.C.), V Foundation for Cancer Research grant (V2015-019 and D2018-010 to C.-J.C.), Purdue AgSEED grant, and NIH P30CA023168 to the Purdue University Center for Cancer Research in support of the use of facilities. M.-J.W. and C.-J.C. designed the study. M.-J.W. Y.-S.C. and C.-J.C. performed the experiments and wrote the manuscript. C.-C.C. S.G. Y.W. Y.Z. and M.R.K. helped with various biochemical and animal studies. C.-Y.C. and J.-Y.Y. provided resources and consultation on imaging experiments. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2019",
month = apr,
day = "2",
doi = "10.1016/j.cmet.2018.11.004",
language = "English",
volume = "29",
pages = "993--1002.e6",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",
}