Abstract
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.