1. Research Background:
One main aim of our group is to investigate the principles underlying neuroinflammation and how cells reacting to injurious insults can be manipulated to promote brain repair. We are particularly interested in glial cells (for instance astrocytes), as these cells play a central role in regulating tissue remodelling following injury. This is true for most neuropathologies characterized by a strong inflammatory component, including traumatic brain injury, ischemia and chronic neurodegeneration, in which astrocytes acquire a reactive state (astrogliosis) underlying important functions in the progression of the injury and its possible resolution, including confining macrophage extravasation and spread of pro-inflammatory mediators. During this response astrocytes exhibit traits of pronounced structural plasticity by acquiring polarized morphologies and potentially resuming proliferation. By combining advanced imaging techniques, omics approaches and mouse genetics, we recently observed that an important layer of regulation of astrocyte reactivity takes places at the level of the mitochondrial network, strongly suggesting that alterations in fission-fusion dynamics underlie changes in the metabolic state and physiological role of reactive astrocytes.
2. Research questions addressed by the group:
- To which extent mitochondrial fission and fusion are required to promote changes in the metabolic state of reactive astrocytes in vivo?
Pro-inflammatory stimuli trigger precise changes in mitochondrial network morphology in astrocytes that evolve during the course of several weeks. However, whether and how these structural changes are accompanied by metabolic switches in fuel utilization and/or biosynthetic pathways in astrocytes which can be important for brain repair remains unclear.
- How are ultrastructural changes in mitochondria of reactive astrocytes achieved and how does this affects astrocyte physiology/signaling in specific subcellular domains?
Astrocytes display a remarkable degree of plasticity with regard to their mitochondrial network morphology and ultrastructure, raising the question of which proteins and molecular cascades mediate these changes during the acquisition of a reactive state. In particular, how these structural changes can be achieved locally in peripheral branches and in turn regulate local signaling important for astrocyte function is unknown.
- Which aspects of brain repair depend upon mitochondrial network remodeling in reactive astrocytes?
Astrocytes regulate key aspects of brain physiology and metabolism (e.g., modulation of synaptic activity and neurovascular coupling), but they also can exert independent toxic and protective roles towards neurons by secreting growth factors, metabolites and even shedding entire organelles. Whether and how changes in the mitochondrial network of reactive astrocytes can trigger specific mechanisms by which astrocytes influence neuronal function and viability is poorly understood.
3. Possible projects:
- Investigating the role of mitochondrial fission and fusion protein in regulating astrocyte reactivity states during brain injury and inflammation.
- Investigating possible instructive roles of reactive astrocytes deriving from mitochondrial network changes onto neuronal viability and function.
4. Applied Methods and model organisms:
The projects will be carried out in transgenic mice and in primary cultures in vitro of glia and neurons. Specific approaches required for the projects and available in the lab are the following ones:
- Imaging (confocal, super-resolution, in vivo 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 imaging techniques, cell culture and mouse handling/tissue processing.
- 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
- 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
- Göbel, J., Motori, E., Bergami, M. (2018). Spatiotemporal control of mitochondrial network dynamics in astroglial cells. Biochem. Biophys. Res. Commun.500, 17-25.
- Motori, E.*, Puyal, J., Toni, N., Ghanem, A., Angeloni, C., Malaguti, M., Cantelli-Forti, G., Berninger, B., Conzelmann, K.K., Götz, M., Winklhofer, K., Hrelia, S., and Bergami, M.* Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. Cell Metab (2013); 18, 844-859. *co-corresponding.