Breakthrough discovery reveals how connection between mitochondrial vulnerability and neurovasculature function impacts neuropsychiatric disease

Philadelphia, August 20, 2025 – In a new study led by the University of Pennsylvania School of Veterinary Medicine (Penn Vet) and Children’s Hospital of Philadelphia (CHOP), researchers found that mitochondrial dysfunction in the blood-brain barrier (BBB) may lead to neuropsychiatric disease in some patients with 22qDS. The researchers also demonstrated that a class of FDA-approved cholesterol drugs could potentially be repurposed to treat this dysfunction. These encouraging findings were published today in the journal Science Translational Medicine.

The BBB is a specialized vascular system that separates the brain from the rest of the body. Maintenance of the BBB is fundamental for optimal brain function, and BBB impairments have been linked to multiple neurological disorders, ranging from autism and schizophrenia to neurodegenerative conditions including multiple sclerosis and Alzheimer’s disease.

One notable feature of the BBB is the elevated mitochondrial content compared with peripheral endothelial cells, which form the inner lining of blood vessels. While mitochondrial dysfunction has been associated with neurodevelopmental and neurodegenerative disorders, little is known about its role in the BBB. To explore this in greater detail, researchers decided to focus on 22qDS, also known as DiGeorge syndrome. This genetic condition, involving six mitochondrial genes, raises the risk for neurodevelopmental and neurodegenerative diseases. Patients have a 25-fold increased risk of developing psychosis, and one in four individuals with this syndrome develop schizophrenia.

CHOP has the world's largest clinic dedicated to the care of children, adolescents and some adults with 22qDS, and a dedicated team of researchers at Penn and CHOP studies the condition as a window into the deeper mysteries of neurodevelopmental disease.

“We previously established that the BBB is compromised in 22qDS, indicating that the crosstalk between the brain and the periphery can be affected,” says co-senior study author Jorge Iván Alvarez, PhD, an associate professor of pathobiology at Penn Vet. “With these findings in mind, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction in 22qDS.”

“This study really demonstrates the power of collaboration,” said co-senior study author Stewart A. Anderson, MD, Associate Chair for Research in the department of Child and Adolescent Psychiatry and Behavioral Sciences at CHOP and associate director of the CHOP/Penn Lifespan Brain Institute. “By combining our respective expertise on mitochondrial function and the BBB, we have made an important discovery that may substantially help individuals with 22qDS.”

The researchers indeed found impairment, suggesting a “leaky” BBB, using a combination of human induced pluripotent stem cell-derived brain microvascular endothelial cells from patients with 22qDS and in BBB endothelial cells from a preclinical model of 22qDS.

Perhaps most exciting, the researchers found that treatment with the drug bezafibrate, a cholesterol drug that is also an activator of mitochondrial generation and turnover, can enhance BBB function in both the stem cell system and in the preclinical model of 22qDS. Treatment in the preclinical model also corrected their deficit in social memory, an abnormality associated with BBB dysfunction as well as schizophrenia. These findings suggest that this class of drugs could potentially be repurposed if the findings are confirmed in clinical trials. While 22qDS was the focus of this study, Drs. Anderson and Alvarez and their teams believe that the findings may have implications for the targetable role of mitochondrial dysfunction in the BBB in other neuropsychiatric conditions, including the development of psychosis outside of the context of 22qDS.

This study was supported by the Uytengsu-Hamilton 22q11 Neuropsychiatry Research Program of the Maternal and Child Health Research Institute (MCHRI) at Stanford University UH22QEXTFY22-03; the National Institutes of Health (NIH) grant to the Institute of Translational Medicine and Therapeutics (ITMAT) and by the Transdisciplinary Awards Program in Translational Medicine and Therapeutics (TAPITMAT) of the University of Pennsylvania NCATS 5UL1TR001878-04; NIH grants R01MH134797-01, R01MH134893-01, R01MH110185-03, R01MH066912 and R37NS048471; the NIH–National Institute of Mental Health BRAIN initiative grant F32MH125600; the Penrose Family; the Howard Hughes Medical Institute; the Blavatnik Family Foundation graduate fellowship; the Multiple Sclerosis Canada–endMS Postdoctoral Fellowship; and the Brain and Behavior Research Foundation.

Crockett et al, “Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome.” Sci Transl Med. Online August 20, 2025. DOI: 10.1126/scitranslmed.ads2116.

About Children’s Hospital of Philadelphia: 
A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.

About the University of Pennsylvania School of Veterinary Medicine

Ranked among the top ten veterinary schools worldwide, the University of Pennsylvania School of Veterinary Medicine (Penn Vet) is a global leader in veterinary education, research, and clinical care. Founded in 1884, Penn Vet is the first veterinary school developed in association with a medical school. The school is a proud member of the One Health initiative, linking human, animal, and environmental health.

Penn Vet’s scientists are a key part of the biomedical community at the University of Pennsylvania (Penn), and they bring a valuable veterinary component to the table. Universally recognized for its work in cancer and regenerative medicine, Penn Vet, which lists 16 of its faculty as members of Penn’s Institute for Regenerative Medicine, has long had a close relationship with Penn’s Perelman School of Medicine. In addition to its strengths in biomedicine, Penn Vet has a distinctive niche in infectious disease research, particularly in the areas of immunology and host-pathogen interactions.

Penn Vet serves a diverse population of animals at its two campuses, which include extensive diagnostic and research laboratories. Ryan Hospital in Philadelphia provides care for companion animals, handling more than 34,600 patient visits a year. New Bolton Center, Penn Vet’s large-animal hospital on 700 acres in rural Kennett Square, PA, cares for horses, livestock, and farm animals. The hospital handles more than 6,200 patient visits a year, while the Field Service unit averages 5,500 farm service calls, treating some 18,700 patients at local farms. In addition, New Bolton Center’s campus includes a swine center, working dairy, and poultry unit that provide valuable research for the agriculture industry.