title: Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada.
authors.forename: Mireille
authors.initials: M
authors.lastname: Khacho
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada.
authors.forename: Alysen
authors.initials: A
authors.lastname: Clark
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada.
authors.forename: Devon S
authors.initials: DS
authors.lastname: Svoboda
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada.
authors.forename: Joelle
authors.initials: J
authors.lastname: Azzi
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada.
authors.forename: Jason G
authors.initials: JG
authors.lastname: MacLaurin
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Meghaizel
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Lagace
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Germain
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada. Electronic address: rslack@uottawa.ca.
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics*; D000066673:Cell Self Renewal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000378:metabolism; D017353:Gene Deletion; D055432:Metabolomics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases