Upregulation of PPTC7 in brain microvascular endothelial cell aggravates diabetic cognitive dysfunction by impairing PHB2 mediated mitochondrial function

Blood-brain barrier impairment (BBB) is the pathological basis of diabetic cognitive dysfunction. Brain microvascular endothelial cells (BMECs) are one of the most mitochondria-rich cell types within the BBB. Mitochondrial dysfunction in BMECs is defined as a pivotal event in diabetic cognitive dysfunction; however, the underlying mechanisms remain poorly understood. Protein phosphatase targeting COQ7 (PPTC7) was screened from RNA-sequencing analysis and its role in regulating mitochondrial function was in both in vitro and in vivo models. PPTC7 expression was predominantly upregulated in BMECs of type 2 diabetes mellitus mice. Genetic manipulations using short hairpin RNA and endothelial-specific adeno-associated virus were applied to investigate the effects of PPTC7 in diabetic cognitive dysfunction. PPTC7 deficiency upregulated mitochondrial oxidative phosphorylation, mitochondrial membrane potential, and mitophagy, but downregulated mitochondrial reactive oxygen species levels in BMECs. Mechanistically, mass spectrometry screening and co-immunoprecipitation assays demonstrated the interaction of PPTC7 with prohibitin 2 (PHB2). PPTC7 disrupts mitochondrial function in BMECs via PHB2 by promoting its ubiquitin-proteasome degradation, which in turn aggravates BBB damage and contributes to diabetic cognitive dysfunction.