Neurovascular mitochondrial susceptibility impacts blood-brain barrier function and behavior

Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared to peripheral endothelial cells, although the functional implications of this phenomenon remain unknown. Here we studied BBB mitochondrial function in the context of the 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. As the 22q11.2 deletion includes 6 mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and impact behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)-derived BBB endothelial cells from 22qDS patients, and in BBB endothelial cells from a mouse model of 22qDS. Remarkably, treatment to improve mitochondrial function attenuates mitochondrial deficits and enhances BBB function in both the iPSC and mouse 22qDS models. This treatment also corrected social memory in the mouse model, a deficit previously associated with BBB dysfunction. As BBB integrity correlated with social memory performance, together our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior in 22qDS. Overall design: RNAseq profiling of brain enodthelial total RNA isolated from 22qDS untreated mice and 22qDS mice given 0.5% bezafibrate-enriched chow.