PT - JOURNAL ARTICLE AU - Gulzar A. Wani AU - Hans-Georg Sprenger AU - Kristiano Ndoci AU - Srikanth Chandragiri AU - Richard James Acton AU - Désirée Schatton AU - Sandra M.V. Kochan AU - Vignesh Sakthivelu AU - Milica Jevtic AU - Jens M. Seeger AU - Stefan Müller AU - Patrick Giavalisco AU - Elena I. Rugarli AU - Elisa Motori AU - Thomas Langer AU - Matteo Bergami TI - Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L AID - 10.1101/2021.08.18.456709 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.08.18.456709 4099 - http://biorxiv.org/content/early/2021/08/19/2021.08.18.456709.short 4100 - http://biorxiv.org/content/early/2021/08/19/2021.08.18.456709.full AB - The transition between quiescence and activation in neural stem and progenitor cells (NSPCs) is coupled to reversible changes in energy metabolism with key implications for life-long NSPC self-renewal and neurogenesis. How this metabolic plasticity is ensured between NSPC activity states is unclear. We found that a state-dependent rewiring of the mitochondrial proteome by the peptidase YME1L is required to preserve NSPC self-renewal in the adult brain. YME1L-mediated proteome rewiring regulates the rate of fatty acid oxidation (FAO) for replenishing Krebs cycle intermediates and dNTP precursors, which are required to sustain NSPC amplification. Yme1l deletion irreversibly shifts the metabolic profile of NSPCs away from a FAO-dependent state resulting in defective self-renewal, premature differentiation and NSPC pool depletion. Our results disclose an important role for YME1L in coordinating the switch between metabolic states of NSPCs and suggest that NSPC fate is regulated by compartmentalized changes in protein network dynamics.Competing Interest StatementThe authors have declared no competing interest.