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While ECs are generally thought to rely primarily on glycolysis for energy production, the transcriptional mechanisms underlying their metabolic specialization in the brain endothelium remain poorly understood, especially considering the brain's extraordinary energy demands. Through comparative transcriptomic analysis, it is demonstrated that brain endothelial cells are enriched for mitochondrial function genes, with forkhead box protein 1 (FOXQ1) being selectively expressed in cerebral vasculature. Conditional knockout of\n                    <jats:italic>Foxq1<\/jats:italic>\n                    in endothelial cells results in severe mitochondrial dysfunction, including disrupted cristae morphology, reduced oxygen consumption, and impaired adenosine triphosphate (ATP) production. Mechanistically, FOXQ1 directly regulates two key pathways: calcium signaling through huntingtin\u2010associated protein (HAP1)\u2010mediated endoplasmic reticulum (ER)\u2010mitochondrial calcium transfer, and mitochondrial structural integrity via AarF domain\u2010containing protein kinase 1 (ADCK1)\u2010dependent cristae organization. These findings reveal that brain endothelial cells rely on oxidative phosphorylation rather than glycolysis alone, challenging the prevailing metabolic paradigm for endothelial cells. This work establishes FOXQ1 as an important regulator of brain endothelial metabolism and provides new insights into the molecular basis of cerebrovascular specialization, with implications for understanding vascular dysfunction in neurological diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202503082","type":"journal-article","created":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T18:06:01Z","timestamp":1756577161000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["FOXQ1 Regulates Brain Endothelial Mitochondrial Function by Orchestrating Calcium Signaling and Cristae Morphology"],"prefix":"10.1002","volume":"12","author":[{"given":"Wenzheng","family":"Zou","sequence":"first","affiliation":[{"name":"Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease Affiliated Hospital of Guangdong Medical University  Zhanjiang 523710 China"},{"name":"Key Laboratory of Organ Regeneration and 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