PT  - JOURNAL ARTICLE
AU  - Jana Göbel
AU  - Patric Pelzer
AU  - Esther Engelhardt
AU  - Vignesh Sakthivelu
AU  - Hannah M. Jahn
AU  - Milica Jevtic
AU  - Kat Folz-Donahue
AU  - Christian Kukat
AU  - Astrid Schauss
AU  - Christian K. Frese
AU  - Alexander Ghanem
AU  - Karl-Klaus Conzelmann
AU  - Elisa Motori
AU  - Matteo Bergami
TI  - Mitochondrial fusion in reactive astrocytes coordinates local metabolic domains to promote vascular repair
AID  - 10.1101/657999
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 657999
4099  - http://biorxiv.org/content/early/2019/06/03/657999.short
4100  - http://biorxiv.org/content/early/2019/06/03/657999.full
AB  - Astrocytes have emerged for playing key roles in tissue remodeling during brain repair, however the underlying mechanisms remain poorly understood. We show that acute injury and blood-brain barrier disruption trigger the formation of a prominent mitochondrial-enriched compartment in astrocytic end-feet which enables vascular recovery. Integrated imaging approaches revealed that this mitochondrial clustering is part of a metabolic adaptive response regulated by fusion dynamics. Astrocyte-specific deletion of Mitofusin 2 (Mfn2) suppressed perivascular mitochondrial remodeling and altered mitochondria-endoplasmic reticulum tethering domains. Functionally, two-photon imaging experiments showed that these structural changes were mirrored by impaired mitochondrial Ca2+ uptake leading to abnormal cytosolic transients in astrocytic end-feet in vivo. At the tissue level, a severely compromised microvasculature in the lesioned area was rescued by boosting mitochondrial perivascular clustering in MFN2-deficient astrocytes. These data unmask a crucial role for astrocyte mitochondrial dynamics in regulating local metabolic signaling and have important implications for repairing the injured brain.