Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program

Mireille Khacho, Alysen Clark, Devon S. Svoboda, Joelle Azzi, Jason G. MacLaurin, Cynthia Meghaizel, Hiromi Sesaki, Diane C. Lagace, Marc Germain, Mary Ellen Harper, David S. Park, Ruth S. Slack

Research output: Contribution to journalArticlepeer-review

Abstract

Regulated mechanisms of stem cell maintenance are key to preventing stem cell depletion and aging. While mitochondrial morphology plays a fundamental role in tissue development and homeostasis, its role in stem cells remains unknown. Here, we uncover that mitochondrial dynamics regulates stem cell identity, self-renewal, and fate decisions by orchestrating a transcriptional program. Manipulation of mitochondrial structure, through OPA1 or MFN1/2 deletion, impaired neural stem cell (NSC) self-renewal, with consequent age-dependent depletion, neurogenesis defects, and cognitive impairments. Gene expression profiling revealed ectopic expression of the Notch self-renewal inhibitor Botch and premature induction of transcription factors that promote differentiation. Changes in mitochondrial dynamics regulate stem cell fate decisions by driving a physiological reactive oxygen species (ROS)-mediated process, which triggers a dual program to suppress self-renewal and promote differentiation via NRF2-mediated retrograde signaling. These findings reveal mitochondrial dynamics as an upstream regulator of essential mechanisms governing stem cell self-renewal and fate decisions through transcriptional programming.

Original languageEnglish (US)
Pages (from-to)232-247
Number of pages16
JournalCell stem cell
Volume19
Issue number2
DOIs
StatePublished - Aug 4 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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