Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program
| Autor: | Ruth S. Slack, Devon S. Svoboda, David S. Park, Alysen Clark, Mireille Khacho, Hiromi Sesaki, Jason G. MacLaurin, Joelle Azzi, Cynthia Meghaizel, Diane C. Lagace, Mary-Ellen Harper, Marc Germain |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Transcription Genetic NF-E2-Related Factor 2 Mitochondrion Biology Mitochondrial Dynamics GTP Phosphohydrolases 03 medical and health sciences Adenosine Triphosphate Cognition Neural Stem Cells Genetics MFN1 Animals Metabolomics Cell Lineage Cell Self Renewal Transcription factor Cell Nucleus Neurogenesis Cell Biology Neural stem cell Cell biology Mitochondria 030104 developmental biology Retrograde signaling Molecular Medicine Ectopic expression Stem cell Reactive Oxygen Species Gene Deletion Signal Transduction |
| Zdroj: | Cell stem cell. 19(2) |
| ISSN: | 1875-9777 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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