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Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L

Gulzar A. Wani, Hans-Georg Sprenger, Kristiano Ndoci, Srikanth Chandragiri, Richard James Acton, Désirée Schatton, Sandra M.V. Kochan, Vignesh Sakthivelu, Milica Jevtic, Jens M. Seeger, Stefan Müller, Patrick Giavalisco, Elena I. Rugarli, Elisa Motori, Thomas Langer, Matteo Bergami
doi: https://doi.org/10.1101/2021.08.18.456709
Gulzar A. Wani
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
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Hans-Georg Sprenger
2Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.
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Kristiano Ndoci
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
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Srikanth Chandragiri
2Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.
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Richard James Acton
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
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Désirée Schatton
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
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Sandra M.V. Kochan
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
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Vignesh Sakthivelu
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
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Milica Jevtic
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
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Jens M. Seeger
3Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), CECAD Research Center and University Hospital Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
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Stefan Müller
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
4Center for Molecular Medicine, Robert-Koch-Str. 21, 50931 Cologne, Germany
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Patrick Giavalisco
2Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.
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Elena I. Rugarli
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
4Center for Molecular Medicine, Robert-Koch-Str. 21, 50931 Cologne, Germany
5Institute of Genetics, Zülpicher Str. 47a, D-50674, University of Cologne, Germany
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Elisa Motori
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
2Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.
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Thomas Langer
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
2Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.
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Matteo Bergami
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
4Center for Molecular Medicine, Robert-Koch-Str. 21, 50931 Cologne, Germany
5Institute of Genetics, Zülpicher Str. 47a, D-50674, University of Cologne, Germany
6University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, D-50937 Cologne, Germany.
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  • For correspondence: matteo.bergami@uk-koeln.de
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Abstract

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 Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 19, 2021.
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Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L
Gulzar A. Wani, Hans-Georg Sprenger, Kristiano Ndoci, Srikanth Chandragiri, Richard James Acton, Désirée Schatton, Sandra M.V. Kochan, Vignesh Sakthivelu, Milica Jevtic, Jens M. Seeger, Stefan Müller, Patrick Giavalisco, Elena I. Rugarli, Elisa Motori, Thomas Langer, Matteo Bergami
bioRxiv 2021.08.18.456709; doi: https://doi.org/10.1101/2021.08.18.456709
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Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L
Gulzar A. Wani, Hans-Georg Sprenger, Kristiano Ndoci, Srikanth Chandragiri, Richard James Acton, Désirée Schatton, Sandra M.V. Kochan, Vignesh Sakthivelu, Milica Jevtic, Jens M. Seeger, Stefan Müller, Patrick Giavalisco, Elena I. Rugarli, Elisa Motori, Thomas Langer, Matteo Bergami
bioRxiv 2021.08.18.456709; doi: https://doi.org/10.1101/2021.08.18.456709

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