A role for Mfn2 in astrocyte perivascular repair following brain injury Jana Gӧbel1, Patric Pelzer1, Hannah M. Jahn1, Esther Engelhard1, Elisa Motori2, Gulzar Wani1, Christian Frese1, Ilian Atanassov2, Alexander Ghanem3, Karl-Klaus Conzelmann3 and Matteo Bergami1,4 1CECAD Cologne, Germany; 2MPI for Biology of Ageing, Cologne, Germany; 3Max von Pettenkofer Institute and Gene Center, LMU Munich, Germany; 4CMMC Cologne, Germany.
Accumulating evidence suggests that major changes in the metabolic profile of astrocytes underlie their responsiveness to brain injury and disease, however which cellular compartments contribute to these changes is unclear. Here, we report that astrocyte perivascular end-feet, which are hotspots of Ca2+-mediated signaling pathways co-regulating vascular tone and metabolic coupling, are characterized by a dense meshwork of elongated mitochondria and ER tubules forming extensive contact sites in vivo. Following acute brain injury however, these two organelles undergo a marked remodeling along with the emergence of typical hallmarks of astrocytic reactivity. On the one hand, this remodeling entails a net redistribution of ER membranes from peripheral processes towards end-feet. On the other hand, injury induces a time-dependent fragmentation of the mitochondrial network which is then re-established by three-to-four weeks, suggesting mitochondrial fusion dynamics to be critical during tissue recovery. Conditional deletion of Mfn2, which regulates mitochondrial fusion, prevents network re-establishment following injury, and leads to ultrastructural alterations in both mitochondrial and ER tubules at perivascular processes. Physiologically, two-photon Ca2+ imaging of Mfn2-deleted astrocytes expressing either mitochondrial or cytosolic GCamp6f in situ revealed significant alterations with respects to their Ca2+ buffering capacity, which were ultimately mirrored by a reduced frequency of spontaneous cytosolic events within end-feet. These results were corroborated by proteomic analysis of astrocytes isolated from adult mouse cortices, which showed a downregulation of Ca2+ signaling pathways, including calcineurin-mediated and other central signaling cascades. At the tissue level, selective ablation of Mfn2 (but not Mfn1) in reactive astrocytes hindered recovery of injured cortices by preventing complete revascularization, indicating a key role for Mfn2 during perivascular repair.
Funding: ERC-StG-2015 (grant number 67844)
Credits: None available.
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