Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell stem cell, 2016-08, Vol.19 (2), p.232-247

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Mitochondrial dynamics regulates the fate and identity of stem cells•Mitochondrial dynamics regulates stem cell fate by modifying ROS signaling•ROS activate developmental gene expression via an NRF2-dependent retrograde pathway•Aberrant mitochondrial dynamics impairs stem cell self-renewal and maintenance Khacho et al. report that mitochondrial dynamics regulates neural stem cell fate during development and in the adult mouse brain. Using acute loss-of-function approaches to uncouple mitochondrial bioenergetics from the fission/fusion machinery, they find that the latter independently regulates ROS levels upstream of NRF2. Thus, defects in mechanisms that maintain the pool of mitochondria also impair neural stem cell function, which has important implications for aging and neurodegenerative diseases.