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

作者：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.^*

来源：Cell Stem Cell, 2016, 19(2): 232-247.

DOI：10.1016/j.stem.2016.04.015

• ENERGY-METABOLISM
• LIFE-SPAN
• DIFFERENTIATION
• FUSION
• ADULT
• NEUROGENESIS
• MECHANISMS
• EXPRESSION
• MUTATIONS
• DIVISION

Regulated mechanisms of stem cell maintenance are key to preventing stem cell depletion andaging. 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.