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Here, we studied BBB mitochondrial function in the context of 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. Because the 22q11.2 deletion includes six mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and affect behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)\u2013derived brain microvascular endothelial cells (iBMECs) from people with 22qDS and in BBB endothelial cells from a mouse model of 22qDS. We found that treatment with bezafibrate, an activator of mitochondrial biogenesis, attenuates mitochondrial deficits and enhances BBB function in both the iBMECs and a mouse model of 22qDS. This treatment also corrects social memory in the mouse model, a deficit previously associated with BBB dysfunction. Given that BBB integrity correlated with social memory performance, our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior.<\/jats:p>","DOI":"10.1126\/scitranslmed.ads2116","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T17:58:12Z","timestamp":1755712692000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":10,"title":["Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9658-938X","authenticated-orcid":true,"given":"Alexis M.","family":"Crockett","sequence":"first","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9016-3406","authenticated-orcid":true,"given":"Maria C. 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