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

Meng Ju Wu, Yu Syuan Chen, Mi Ran Kim, Chao Ching Chang, Silpa Gampala, Yingsheng Zhang, Yueyang Wang, Chih Yu Chang, Jer Yen Yang, Chun Ju Chang

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)993-1002.e6
JournalCell Metabolism
Volume29
Issue number4
DOIs
Publication statusPublished - Apr 2 2019
Externally publishedYes

Keywords

  • cell plasticity
  • EMT
  • mammary stem cell
  • mitochondrial dynamics
  • mitofusin
  • stem cell fate
  • stem cell polarity

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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