Prof. Dr. Matteo Bergami

Research Area: Neuroinflammation, Glial cell biology, Mitochondrial biology

Branches: MetabolismNeurobiologyStem Cell Biology

1. Research Background:

A main interest of our group is to investigate the principles governing neural stem cell (NSC) activity and pool maintenance in the adult brain. Actively dividing NSCs are maintained in few restricted areas of the adult mammalian brain – like in the hippocampus – where they produce new neurons lifelong. The neurogenic potential of adult NSCs largely depends on their self-renewal capacity, which is required for long-term maintenance of the NSC pool. Recently, work performed in the lab uncovered a novel form of metabolic plasticity that controls NSC self- renewal potential. Taking advantage of unbiased omics and gene manipulation approaches in adult NSCs in vivo and maintained in vitro, we identified specific metabolic programs whose activity is regulated in a NSC state-dependent manner (Wani et al., 2022). In particular, we found that NSCs undergo a profound but reversible rewiring of their mitochondrial proteome during the transition between active and quiescent states seemingly independent from gene transcription changes. Gain and loss of function analyses in vitro and in vivo revealed putative key candidate proteins that may play a central role in driving this proteomic rewiring, which is reflected by changes in mitochondrial fuel utilization, dynamics and structure. The aim of this project is that of investigating the precise contribution of these identified pathways for NSC self-renewal capacity.   

2. Research questions addressed by the group:

  • What is the role of mitochondrial fission and fusion in adult NSCs? By taking advantage of mice allowing the conditional deletion of key regulators of mitochondrial fission and fusion, the aim of this project is that of identifying to which extent and how mitochondrial dynamics regulate NSC self-renewal and fate specification in the adult brain.
  • Do mitochondrial cristae remodel in adult NSCs, how do they do so and what are the implications for NSC activity?
    Starting by conditionally manipulating the GTPase Opa1, and broadening into other effectors of cristae remodeling, this project aims at revealing how changes in cristae may control NSC metabolic activity and fate, in vitro and in vivo in mouse models.
  • How do NSC utilize OXPHOS to regulate their metabolic and activity states? While for long time believed to be essentially glycolytic in nature, the activity and expression of OXPHOS subunits in NSCs have been re-assessed on account of recently published transcriptomics/proteomics datasets in our lab (Wani et al, 2022). However, the functional relevance of OXPHOS for the metabolic state and signaling between active and quiescent NSC is still unknown.

3. Possible projects:

  1. Dissect the role of mitochondrial fission and fusion in adult NSCs.
  2. Dissect the role of mitochondrial cristae remodelling in adult NSCs.
  3. Dissect the role of OXPHOS in adult NSCs.

4. Applied Methods and model organisms:

The projects will be carried out in transgenic mice and in primary cultures in vitro of adult NSCs. Specific approaches required for the projects and available in the lab are:

  • Imaging (confocal, super-resolution, 2-photon microscopy and electron microscopy)
  • Viral approaches to introduce cell-specific gene manipulation
  • Cell sorting, proteomics and metabolomics
  • Brain surgery techniques
  • Mouse genetics

5. Desirable skills and qualifications:

Background in any of the following: stem cell biology, glial cell biology or mitochondrial biology. Knowledge in any of the following: imaging techniques, cell culture, mouse handling/brain tissue processing, bioenergetics.

6. References:

  1. Wani, G., Sprenger, H.G., Ndoci, K., Chandragiri, S., Acton, R.J., Kochan, S.M.V., Schatton, D., Sakthivelu, V., Jevtic, M., Seeger, J.M., Müller, S., Giavalisco, P., Rugarli, E.I., Motori, E., Langer, T., Bergami, M. (2021). Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L. BioRxiv. DOI:https://doi.org/10.1101/2021.08.18.456709.
  2. Göbel, J., Pelzer, P., Engelhardt, E., Sakthivelu, V., Jahn, H.M., Milica, J., Folz-Donahue, K., Schauss, A., Ghanem, A., Conzelmann,, K.K., Frese, C., Motori, E.*, Bergami, M*. (2019). Mitochondrial fusion in reactive astrocytes coordinates local metabolic domains to promote vascular repair. Cell Metab. 31, 791-808. *equal contribution  
  3. Rangaraju, V.*, Lewis, T.*, Hirabayashi, Y.*, Bergami, M.*, Motori, E.*, Cartoni, R.*, Kwon, S.K., and Courchet, J. (2019). Pleiotropic Mitochondria: The influence of mitochondria on neuronal development and disease. J. Neurosci. 39, 8002-8208. *equal contribution
  4. Bergami, M.#, Masserdotti, G., Temprana, S., Motori, E., Eriksson, T.E., Göbel, J., Yang, S.M., Conzelmann, K.K., Schinder, A.F., Götz, M., Berninger, B. A critical period for experience-dependent remodelling of adult-born neuron connectivity. Neuron (2015); 85, 710-717. #corresponding author.