Mitochondrial fusion in reactive astrocytes coordinates local metabolic domains to promote vascular repair

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.