The mitochondrial peptidase YME1L controls the early proliferative steps of adult neurogenesis

Identification: Wani, Gulzar



The mitochondrial peptidase YME1L controls the early proliferative steps of adult neurogenesis
Gulzar A Wani1, Sandra Wendler1, Hans-Georg Sprenger1, Jana Göbel1, Booshini Fernando1, Karl-Klaus Conzelmann2, Thomas Langer1,3,4 and Matteo Bergami1,4,*
1CECAD, University Hospital Cologne, Germany
2Max von Pettenkofer Institute and Gene Center, LMU Munich, Germany
3Institute for Genetics, University of Cologne, Germany
4CMMC, University of Cologne, Germany
*Corresponding Author
The hippocampus is one of the few regions in the adult mammalian brain where neural stem cells (NSCs) give rise to new functional neurons, thus contributing to key aspects of cognition. This process involves the activation of otherwise quiescent NSCs and the generation of fast-dividing, intermediate progenitor cells (IPCs) which then differentiate into neurons. Although the mechanisms regulating this neurogenic process are incompletely understood, emerging evidence suggests that changes in the metabolic state of NSCs may facilitate their progression towards new neurons. In particular, NSC activation and differentiation are mirrored by a corresponding increase in mitochondrial-related genes, suggesting that a shift towards a mitochondrial-dependent energy metabolism underlies important aspects of neurogenesis. Yet, to which extent mitochondrial dynamics and quality control regulate NSC lineage progression is unclear. Here, we show that the i-AAA peptidase YME1L - which is known to co-regulate together with OMA1 the processing of OPA1 at the inner mitochondrial membrane and thus, mitochondrial fusion dynamics - plays a central role in promoting this lineage progression in the adult hippocampus in vivo. Conditional deletion of YME1L induces a marked fragmentation of the mitochondrial network in adult NSCs, which is otherwise characterized by high rates of fusion dynamics.  Loss of YME1L (but not OMA1) impaired the proliferation rate and pool expansion of IPCs, ultimately leading to compromised neurogenesis. Experiments conducted in primary adult NSCs maintained in vitro corroborate these findings and further revealed that the proliferative defects in YME1L-deficient cells are primarily mediated by a marked down-regulation of mitochondrial beta-oxidation. These results provide evidence for the potential interplay between mitochondrial structure and function in adult NSCs in vivo and indicate that YME1L is required during the early stages of NSC lineage progression towards new neurons.
Funding: ERC-StG-2015 (grant 67844)



Credits: None available.

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