Center for Molecular Medicine Cologne

Bergami, Matteo - C 03

Role of metabolic signaling at the glio-vascular interface during brain injury and repair

Introduction

Accruing evidence indicates that glial cells play pivotal roles in maintaining multiple forms of metabolic coupling with neurons and the brain microvasculature. In particular, astrocytic end-feet functionally ensheathe most of the vascular network and serve as specialized exchange sites for ions and energy substrates with brain parenchyma. While in physiological conditions these functions contribute to neurovascular coupling, the precise sub-cellular changes occurring at the glio-vascular interface during brain injury are much less understood.

Building on preliminary data disclosing an important restructuring of the mitochondrial network in perivascular astrocytes reacting to brain injury, a major focus of this funding period has been that of investigating whether and how changes in astrocytic mitochondrial structure and metabolism play a role in tissue remodelling. The collected results revealed an unexpected role of mitochondria and associated organelles in controlling how perivascular astrocytic end-feet regulate angiogenesis and brain tissue repair (Figure 1), laying the ground for assessing and manipulating key metabolic signalling functions at the gliovascular interface.  

Figure 1

Our Aims

  1. Assessing the role of specific mitochondrial-derived signaling pathways in reactive astrocytes 

  2. Characterization of mitochondrial metabolism in reactive astrocytes 

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  • Bergami M, and Motori E. Reweaving the Fabric of Mitochondrial Contact Sites in Astrocytes. Front Cell Dev Biol(2020); 8:592651.
  • Göbel J, Pelzer P, Engelhardt E, Sakthivelu V, Jahn HM, Jevtic M, Folz-Donahue K, Kukat C, Schauss A, Frese CK, Ghanem A, Conzelmann KK, Motori E, Bergami M. Mitochondrial fusion in reactive astrocytes coordinates local metabolic domains to promote vascular repair. BioRxiv (2019); doi: https://doi.org/10.1101/657999.
  • Göbel J, Motori E, Bergami M. Spatiotemporal control of mitochondrial network dynamics in astroglial cells. Biochem Biophys Res Commun(2018); 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; *equal contribution.
  • Wani GA, Sprenger HG, Ndoci K, Chandragiri S, Acton RJ, Schatton D, Kochan SMV, Sakthivelu V, Jevtic M, Seeger JM, Muller S, Giavalisco P, Rugarli EI, Motori E, Langer T, and Bergami M (2022). Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L. Cell Rep38, 110370. doi:10.1016/j.celrep.2022.110370.
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  • Bergami M, and Motori E (2020). Reweaving the Fabric of Mitochondrial Contact Sites in Astrocytes. Front Cell Dev Biol 8, 592651.
  • Göbel J, Engelhardt E, Pelzer P, Sakthivelu V, Jahn HM, Jevtic M, Folz-Donahue K, Kukat C, Schauss A, Frese CK, Giavalisco P, Ghanem A, Conzelmann KK, Motori E*, and Bergami M* (2020). Mitochondria-Endoplasmic Reticulum Contacts in Reactive Astrocytes Promote Vascular Remodeling. Cell Metab 31, 791-808 e8. *equal contribution.
  • Ricke KM, Pass T, Kimoloi S, Fahrmann K, Jungst C, Schauss A, Baris OR, Aradjanski M, Trifunovic A, Eriksson Faelker TM, Bergami M, and Wiesner RJ (2020). Mitochondrial Dysfunction Combined with High Calcium Load Leads to Impaired Antioxidant Defense Underlying the Selective Loss of Nigral Dopaminergic Neurons. J Neurosci 40, 1975-86.