Epithelial-Mesenchymal Transition Directs Stem Cell Polarity via Regulation of Mitofusin

• Published in: Cell metabolism Vol. 29; no. 4; pp. 993 - 1002.e6
• Main Authors: Wu, Meng-Ju, Chen, Yu-Syuan, Kim, Mi Ran, Chang, Chao-Ching, Gampala, Silpa, Zhang, Yingsheng, Wang, Yueyang, Chang, Chih-Yu, Yang, Jer-Yen, Chang, Chun-Ju
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.04.2019
• Subjects: cell plasticity; EMT; mammary stem cell; mitochondrial dynamics; mitofusin; stem cell fate; stem cell polarity; stem cell fate; mammary stem cell; cell plasticity; EMT; mitofusin; stem cell polarity; mitochondrial dynamics
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2018.11.004

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. [Display omitted] •EMT induces mitochondrial fusion through upregulation of MFN1•MFN1 is required for PKCζ-mediated NUMB phosphorylation for asymmetric cell division•MFN1-PKCζ tethers fused mitochondria for segregation into stem cell progeny•Mitochondrial fusion enhances GSH synthesis to promote stem cell self-renewal 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.